Macrocyclic hepatitis C serine protease inhibitors

ABSTRACT

The present invention relates to novel macrocyclic compounds and methods of treating a hepatitis C infection in a subject in need of such therapy with said macrocyclic compounds. The present invention further relates to pharmaceutical compositions comprising the compounds of the present invention, or pharmaceutically acceptable salts, esters, or prodrugs thereof, in combination with a pharmaceutically acceptable carrier or excipient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 13/439,551, filed Apr. 4, 2012, allowed, which is a continuationapplication of U.S. application Ser. No. 12/584,716, filed Sep. 10,2009, issued as U.S. Pat. No. 8,420,596, issued Apr. 16, 2013, whichclaims the benefit of U.S. provisional patent application Ser. No.61/191,725, filed Sep. 11, 2008, and U.S. provisional patent applicationSer. No. 61/209,689, filed Mar. 10, 2009. The disclosures of theaforementioned patent applications are incorporated herein in theirentirety by this reference.

JOINT RESEARCH AGREEMENT

Inventions described in this application were made by or on behalf ofAbbott Laboratories and Enanta Pharmaceuticals, Inc. whom are parties toa joint research agreement, that was in effect on or before the datesuch inventions were made and such inventions were made as a result ofactivities undertaken within the scope of the joint research agreement.

TECHNICAL FIELD

The present invention relates to novel macrocycles having activityagainst the hepatitis C virus (HCV) and useful in the treatment of HCVinfections. More particularly, the invention relates to macrocycliccompounds, compositions containing such compounds and methods for usingthe same, as well as processes for making such compounds.

BACKGROUND OF THE INVENTION

HCV is the principal cause of non-A, non-B hepatitis and is anincreasingly severe public health problem both in the developed anddeveloping world. It is estimated that the virus infects over 200million people worldwide, surpassing the number of individuals infectedwith the human immunodeficiency virus (HIV) by nearly five fold. HCVinfected patients, due to the high percentage of individuals inflictedwith chronic infections, are at an elevated risk of developing cirrhosisof the liver, subsequent hepatocellular carcinoma and terminal liverdisease. HCV is the most prevalent cause of hepatocellular cancer andcause of patients requiring liver transplantations in the western world.

There are considerable barriers to the development of anti-HCVtherapeutics, which include, but are not limited to, the persistence ofthe virus, the genetic diversity of the virus during replication in thehost, the high incident rate of the virus developing drug-resistantmutants, and the lack of reproducible infectious culture systems andsmall-animal models for HCV replication and pathogenesis. In a majorityof cases, given the mild course of the infection and the complex biologyof the liver, careful consideration must be given to antiviral drugs,which are likely to have significant side effects.

SUMMARY OF THE INVENTION

The present invention relates to novel macrocyclic compounds and methodsof treating a hepatitis C infection in a subject in need of such therapywith said macrocyclic compounds. The compounds of the present inventioninterfere with the life cycle of the hepatitis C virus and are useful asantiviral agents. The present invention further relates topharmaceutical compositions comprising the compounds of the presentinvention, or pharmaceutically acceptable salts, esters or prodrugsthereof, in combination with a pharmaceutically acceptable carrier orexcipient.

In one aspect, the invention provides a compound of formula I or formulaI′:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein:

J is absent, optionally substituted alkylene, optionally substitutedalkenylene, optionally substituted alkynylene, —C(O)—, —O—C(O)—,—N(R₃)—C(O)—, —C(S)—, —C(═NR₄—, —S(O)—, —S(O₂)—, or —N(R₃)—;

A is optionally substituted alkyl, optionally substituted alkenyl, oroptionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl,optionally substituted arylalkyl, optionally substituted alkoxy,optionally substituted heteroaryl, optionally substituted heterocyclic,or optionally substituted carbocyclic;

Each R₁ is independently selected from

-   -   (i) halogen, hydroxy, amino, —CN, —CF₃, —N₃, —NO₂, —OR₄, —SR₄,        —SOR₄, —SO₂R₄, —N(R₃)S(O₂)—R₄, —N(R₃) S(O₂)NR₃R₄, —NR₃R₄,        —C(O)OR₄, —C(O)R₄, —C(O)NR₃R₄, or —N(R₃)C(O)R₄;    -   (ii) optionally substituted aryl;    -   (iii) optionally substituted heteroaryl;    -   (iv) optionally substituted heterocyclic;    -   (v) optionally substituted carbocyclic; or    -   (vi) optionally substituted alkyl, optionally substituted        alkenyl, or optionally substituted alkynyl, each containing 0,        1, 2, or 3 heteroatoms selected from O, S, or N;

G is -E-R₅;

-   -   wherein E is absent; optionally substituted alkylene, optionally        substituted alkenylene, optionally substituted alkynylene, each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        or —O—, —S—, —N(R₃)—, —N(R₃)S(O_(p))—, —N(R₃)C(O)—, —N(R₃)        C(O)S(O_(p))—, —OS(O_(p))—, —C(O)S(O)—, or —C(O)N(R₃)S(O_(p))—;    -   p is 0, 1, or 2;    -   R₅ is H; optionally substituted alkyl, optionally substituted        alkenyl, or optionally substituted alkynyl, each containing 0,        1, 2, or 3 heteroatoms selected from O, S, or N; optionally        substituted carbocyclic, optionally substituted heterocyclic,        optionally substituted aryl, or optionally substituted        heteroaryl;

R₃ and R₄ are each independently selected at each occurrence from thefollowing: optionally substituted alkyl, optionally substituted alkenylor optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

L is absent or is selected from optionally substituted alkylene,optionally substituted alkenylene or optionally substituted alkynylene,each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N:

Y is N or —C(R″)—;

wherein A, R₁, R′ and/or R″ can be taken together to form a ring;

j=0, 1, 2, 3, or 4;

k=0, 1, 2, or 3;

m=0, 1, or 2;

n is 0, 1, 2, 3, or 4; and

denotes a carbon-carbon single or double bond,

wherein if Y is N, then R′ is optionally substituted heterocyclic,optionally substituted heteroaryl, optionally substituted aryl oroptionally substituted carbocyclic, and comprises two or more fusedrings, and wherein R′ is not or;

wherein if Y is —C(R″)—, then R′ and R″ taken together with the carbonatoms to which they are attached form an aryl or heteroaryl ring, eachsaid ring is optionally substituted;

provided that said compound is not tert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate.

In another aspect, the invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula Ior I′, or a pharmaceutically acceptable salt, ester, or prodrug thereof,in combination with a pharmaceutically acceptable carrier or excipient.

In one aspect, the invention provides a method of treating a viralinfection in a subject, comprising administering to the subject atherapeutically effective amount of a compound of formula I or I′, or apharmaceutically acceptable salt, ester or prodrug thereof, or apharmaceutical composition comprising the same.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a compound of formula I or I′:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein:

J is absent, optionally substituted alkylene, optionally substitutedalkenylene, optionally substituted alkynylene, —C(O)—, —O—C(O)—,—N(R₃)—C(O)—, —C(S)—, —C(═NR₄)—, —S(O)—, —S(O₂)—, or —N(R₃)—;

A is optionally substituted alkyl, optionally substituted alkenyl, oroptionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl,optionally substituted arylalkyl, optionally substituted alkoxy,optionally substituted heteroaryl, optionally substituted heterocyclic,or optionally substituted carbocyclic;

Each R₁ is independently selected from

-   -   (i) halogen, hydroxy, amino, —CN, —CF₃—N₃, —NO₂, —OR₄, —SR₄,        —SOR₄, —SO₂R₄, —N(R₃)S(O₂)—R₄, —N(R₃) S(O₂)NR₃R₄, —NR₃R₄,        —C(O)OR₄, —C(O)R₄, —C(O)NR₃R₄, or —N(R₃)C(O)R₄;    -   (ii) optionally substituted aryl;    -   (iii) optionally substituted heteroaryl;    -   (iv) optionally substituted heterocyclic;    -   (v) optionally substituted carbocyclic; or    -   (vi) optionally substituted alkyl, optionally substituted        alkenyl, or optionally substituted alkynyl, each containing 0,        1, 2, or 3 heteroatoms selected from O, S, or N;

G is -E-R₅;

-   -   wherein E is absent; optionally substituted alkylene, optionally        substituted alkenylene, optionally substituted alkynylene, each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        or —O—, —S—, —N(R₃)—, —N(R₃)S(O_(p))—, —N(R₃)C(O)—, —N(R₃)        C(O)S(O_(p))—, —OS(O_(p))—, —C(O)S(O_(p))—, or        —C(O)N(R₃)S(O_(p))—;    -   p is 0, 1, or 2;    -   R₅ is H; optionally substituted alkyl, optionally substituted        alkenyl, or optionally substituted alkynyl, each containing 0,        1, 2, or 3 heteroatoms selected from O, S, or N; optionally        substituted carbocyclic, optionally substituted heterocyclic,        optionally substituted aryl, or optionally substituted        heteroaryl;

R₃ and R₄ are each independently selected at each occurrence from thefollowing: optionally substituted alkyl, optionally substituted alkenylor optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

L is absent or is selected from optionally substituted alkylene,optionally substituted alkenylene or optionally substituted alkynylene,each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;

Y is N or —C(R″)—;

wherein A, R₁, R′ and/or R″ can be taken together to form a ring;

j=0, 1, 2, 3, or 4;

k=0, 1, 2, or 3;

m=0, 1, or 2;

n is 0, 1, 2, 3, or 4; and

denotes a carbon-carbon single or double bond

wherein if Y is N, then R′ is optionally substituted heterocyclic,optionally substituted heteroaryl, optionally substituted aryl oroptionally substituted carbocyclic, and comprises two or more fusedrings, and wherein R′ is not

wherein if Y is —C(R″)—, then R′ and R″ taken together with the carbonatoms to which they are attached form an aryl or heteroaryl ring, eachof which is optionally substituted;

provided that said compound is not tert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate.

It is understood that the embodiments of the invention discussed belowwith respect to the preferred variable selections can be taken alone orin combination with one or more of the other embodiments, or preferredvariable selections, of the invention, as if each combination wereexplicitly listed herein.

In one aspect, the invention provides a compound of formula I or I′, ora pharmaceutically acceptable salt, ester or prodrug thereof, wherein Yis CR″, and R′ and R″ taken together with the carbon atoms to which theyare attached form an optionally substituted aryl or an optionallysubstituted heteroaryl ring.

In another aspect, the invention provides a compound of formula I or I′,or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinY is CR″, and R′ and R″ taken together with the carbon atoms to whichthey are attached form an optionally substituted aryl ring, preferablyphenyl.

Alternatively or additionally, k=3, j=1 and L is absent.

Alternatively or additionally, R′ and R″, and the atoms to which each isattached, form an aryl which is substituted by (R₂)_(x), wherein each R₂is independently selected from halogen, hydroxy, amino, —CN, —CF₃, —N₃,—NO₂, —OR₄, —SR₄, —SOR₄, —SO₂R₄, —N(R₃)S(O₂)—R₄, —N(R₃) S(O₂)NR₃R₄,—NR₃R₄, —C(O)OR₄, —C(O)R₄, —C(O)NR₃R₄, or —N(R₃)C(O)R₄; optionallysubstituted aryl; optionally substituted heteroaryl; optionallysubstituted heterocyclic; optionally substituted carbocyclic; oroptionally substituted alkyl, optionally substituted alkenyl, oroptionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; and x is 0, 1, 2, 3, or 4.

Alternatively or additionally, R₁ is absent (i.e., n=−0) or is halogen,hydroxy, amino, —CN, —CF₃, —N₃, —NO₂, —OR₄, —SR₄, —SOR₄, —SO₂R₄,—N(R₃)S(O₂)—R₄, —N(R₃) S(O₂)NR₃R₄, —NR₃R₄, —C(O)OR₄, —C(O)R₄,—C(O)NR₃R₄, or —N(R₃)C(O)R₄.

Alternatively or additionally, R′ and R″, and the atoms to which each isattached, form an aryl which is substituted by (R₂)_(x), wherein each R₂is independently absent (i.e., x=−0) or halogen.

Alternatively or additionally, R₁ is absent (i.e., n=0) or halogen.

Alternatively or additionally, E is —NH—, —NHS(O_(P))—, or—NH(CO)S(O_(p))—, and p is 2.

Alternatively or additionally, E is —NHS(O_(p))—, and p is 2.

Alternatively or additionally, R₅ is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, pyrimidinyl, furanyl,thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperidinyl,piperazinyl, or imidazolyl, each of which is optionally substituted. Ina further embodiment, R₅ is optionally substituted cyclopropyl oroptionally substituted thienyl, preferably cyclopropyl or thienyl.

Alternatively or additionally, J is —C(O)—, —O—C(O)—, —C(S)—, —C(═NR₄)—,—S(O)—, or —S(O₂)—. Preferably, J is —C(O)—.

Alternatively or additionally, m is 1.

Alternatively or additionally, each R₃ is H.

Alternatively or additionally, A is optionally substituted —C₁-C₈ alkyl,containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;optionally substituted aryl, optionally substituted —C₁-C₈ alkoxy,optionally substituted heteroaryl, optionally substituted —C₃-C₁₂cycloalkyl, or optionally substituted —C₃-C₁₂ heterocycloalkyl. In afurther embodiment, A is selected from

Preferably, A is a 5-methyl-pyrazin-2-yl.

In still another aspect, the invention provides a compound of formula Ior I′, or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein Y is CR″, and R′ and R″ taken together with the carbon atoms towhich they are attached form an optionally substituted heteroaryl ring.The remaining variables are as defined above, including the alternativeor preferred embodiments, as if repeated herein.

The invention also features a compound of formula I or I′ (preferablyformula I), or a pharmaceutically acceptable salt, ester or prodrugthereof, wherein Y is CR″, and R′ and R″ taken together with the carbonatoms to which they are attached form an aryl or heteroaryl ring,preferably phenyl, which is optionally substituted with one or more R₂;

k=0, j=0, m=1, n=−0, 1, 2, 3 or 4, and L is C₃-C₆alkylene,C₃-C₆alkenylene or C₃-C₆alkynylene and is optionally substituted withone or more R₇ (preferably butylene);

J is —C(O)— or —O—C(O)— (preferably —C(O)—);

A is C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀carbocyclic, aryl,heteroaryl or heterocyclic comprising 5 to 10 ring atoms, and A isoptionally substituted with one or more R₆;

G is -E-R₅, E is —NHS(O₂)—; R₅ is C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₁₀carbocyclic (preferably cyclopropyl), heteroaryl(preferably thienyl) or heterocyclic comprising 5 to 10 ring atoms, andR₅ is optionally substituted with one or more R₇:

each R₁ and R₂ is independently selected from halogen, hydroxy, amino,—CN, —CF₃, —N₃, —NO₂, —OR₄, —SR₄, —S(O)R₄, —S(O₂)R₄, —NR₃R₄, —C(O)OR₄,—C(O)R₄, —C(O)NR₃R₄, —N(R₃)C(O), C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl. C₂-C₆haloalkenyl, C₂-C₆haloalkynyl, C₃-C₁₀carbocyclicoptionally substituted with one or more R₇, or heterocyclic comprising 5to 10 ring atoms and optionally substituted with one or more R₇,

wherein each R₆ and R₇ is independently selected at each occurrence fromhalogen, hydroxy, amino, —CF₃, —CN, —N₃, —NO₂, —C₁-C₆alkyl (preferablymethyl), C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl,or C₂-C₆haloalkynyl (and, preferably, R₁ and R₂ is absent in eachinstance); and

R₃ and R₄ are each independently selected at each occurrence fromhydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl and R₃ is preferablyhydrogen.

The invention further features a compound of formula I or I′ (preferablyformula I), or a pharmaceutically acceptable salt, ester or prodrugthereof, wherein Y is CR″, R′ and R″ taken together with the carbonatoms to which they are attached form a phenyl optionally substitutedwith one or more R₂;

k=3, j=1, m=1, n=0, 1, 2, 3, or 4, and L is absent;

J is —C(O)— or —O—C(O)—;

A is C₁-C₆alkyl, aryl, heteroaryl, C₅-C₆carbocyclic or heterocycliccomprising 5 to 6 ring atoms, and is optionally substituted with one ormore R₆;

G is -E-R₅, E is —NHS(O₂)—; R₅ is C₃-C₆carbocyclic or heteroaryl, and isoptionally substituted with one or more R₇; in one embodiment, R₅ isselected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, orimidazolyl, each of which is optionally substituted with one or more R₇;preferably, R₅ is cyclopropyl;

each R₁ and R₂ is independently selected from halogen, hydroxy, amino,—CN, —N₃, —CF₃, —NO₂, —OR₄, —SR₄, —S(O)R₄, —S(O₂)R₄, —NR₃R₄, —C(O)OR₄,—C(O)R₄, —C(O)NR₃R₄, —N(R₃)C(O)R₄, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, or C₂-C₆haloalkynyl;

R₃ is hydrogen; and each R₄ is independently selected from hydrogen,C₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;

R₆ and R₇ is independently selected at each occurrence from halogen,hydroxy, amino, —CF₃, —CN, —N₃, —NO₂, —C₁-C₆alkyl (preferably methyl),C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, orC₂-C₆haloalkynyl;

A can be, for example, selected from the following groups, each groupoptionally substituted with one or more R₆:

In yet another aspect, the invention provides a compound of formula I orI′, or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein R′ is optionally substituted heterocyclic, optionallysubstituted heteroaryl, optionally substituted aryl or optionallysubstituted carbocyclic, and comprises two or more fused rings, andwherein R′ is not

and Y is N.

In still another aspect, the invention provides a compound of formula Ior I′, or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein R′ is an optionally substituted heterocyclic or optionallysubstituted heteroaryl, comprises two or more fused rings, and whereinR′ is not

and Y is N. Preferably, R′ is an optionally substituted fused bicyclicheterocyclic or fused bicyclic heteroaryl. Alternatively oradditionally, R′ is an optionally substituted with one or more R₂, andpreferably with an alkyl or aryl.

The remaining variables are as defined above, including in the preferredand alternative embodiments.

In another aspect, the invention provides a compound of formula I or I′or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinR′ is optionally substituted heterocyclic, optionally substitutedheteroaryl, optionally substituted aryl or optionally substitutedcarbocyclic, and comprises two or more fused rings, and wherein R′ isnot

and Y is N; wherein k=3, j=1 and L is absent.

Preferably, the compound has formula I.

Alternatively or additionally, m is 1.

Alternatively or additionally, each R₃ is H.

Alternatively or additionally, R₁ and R₂ are independently hydrogen orhalogen.

Alternatively or additionally, E is —NHS(O_(p))—, and p is 2.

Alternatively or additionally, R₅ is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, pyrimidinyl, furanyl,thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperidinyl,piperazinyl, or imidazolyl, each of which is optionally substituted. Ina further embodiment, R₅ is optionally substituted cyclopropyl oroptionally substituted thienyl, and preferably cyclopropyl or thienyl.

Alternatively or additionally, J is —C(O)—.

Alternatively or additionally, A is optionally substituted —C₁-C₈ alkyl,containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;optionally substituted aryl, optionally substituted —C₁-C₈ alkoxy,optionally substituted heteroaryl, optionally substituted —C₃-C₁₂cycloalkyl, or optionally substituted —C₃-C₁₂ heterocycloalkyl. In afurther embodiment, A is selected from

In another aspect, the invention provides a compound of formula I or I′or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinY is N, and R′ is

and is optionally substituted; provided that said compound is nottert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate.

The invention also features a compound of formula I or formula I′(preferably formula I), or a pharmaceutically acceptable salt, ester orprodrug thereof, wherein Y is N, and R′ is

and is optionally substituted with one or more R₂;

k=0, j=0, m=1, n=0, 1, 2, 3, or 4, and L is C₃-C₆alkylene,C₃-C₆alkenylene or C₃-C₆alkynylene and is optionally substituted withone or more R₇;

J is —C(O)— or —O—C(O)—;

A is C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀-carbocyclic, aryl,heteroaryl, or heterocyclic comprising 5 to 10 ring atoms, and A isoptionally substituted with one or more R₆;

G is -E-R₅, E is —NHS(O₂)—; R₅ is C₂-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₁₀carbocyclic, aryl, heteroaryl, or heterocycliccomprising 5 to 10 ring atoms, and R₅ is optionally substituted with oneor more R₇;

each R₁ and R₂ is independently selected from halogen, hydroxy, amino,—CN, —CF₃, —N₃, —NO₂, —OR₄, —SR₄, —S(O)R₄, —S(O₂)R₄, —NR₃R₄, —C(O)OR₄,—C(O)R₄, —C(O)NR₃R₄, —N(R₃)C(O)R₄, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C₃-C₁₀carbocyclic optionally substituted with one or more R₇, orheterocyclic comprising 5 to 10 ring atoms and optionally substitutedwith one or more R₇,

wherein each R₆ and R₇ is independently selected from halogen, hydroxy,amino, —CN, —CF₃, —N₃, —NO₂, —C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl, or C₂-C₆haloalkynyl; and R₃ or R₄ areeach independently selected at each occurrence from hydrogen,C₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl;

provided that said compound is not tert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate.

The invention further features a compound of formula I or formula I′(preferably formula I), or a pharmaceutically acceptable salt, ester orprodrug thereof, wherein Y is N, and R′ is

and is optionally substituted with one or more R₂;

k=0, j=0, m=1, n=0, 1, 2, 3, or 4, and L is C₃-C₆alkylene,C₃-C₆alkenylene or C₃-C₆alkynylene and is optionally substituted withone or more halo;

J is —C(O)— or —O—C(O)—; A is C₁-C₆alkyl, aryl, heteroaryl,C₃-C₁₀carbocyclic or heterocyclic comprising 5 to 10 ring atoms, and isoptionally substituted with one or more R₆;

G is -E-R₅, E is —NHS(O₂)—; R₅ is C₃-C₁₀carbocyclic or heteroaryl, andis optionally substituted with one or more R₇;

each R₁ and R₂ are independently selected from halogen, hydroxy, amino,—CN, —CF₃, —N₃, —NO₂, —OR₄, —SR₄, —S(O)R₄, —S(O₂)R₄, —NR₃R₄, —C(O)OR₄,—C(O)R₄, —C(O)NR₃R₄, —N(R₃)C(O)R₄, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, C₂-C₆haloalkynyl,C₃-C₁₀carbocyclic optionally substituted with one or more R₇, orheterocyclic comprising 5 to 10 ring atoms and optionally substitutedwith one or more R₇,

wherein each R₆ and R₇ is independently selected from halogen, hydroxy,amino, —CN, —CF₃, —N₃, —NO₂, —C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆haloalkyl, C₂-C₆haloalkenyl, or C₂-C₆haloalkynyl; R₃ is hydrogen;and each R₄ is independently selected from hydrogen, C₁-C₆alkyl,C₂-C₆alkenyl, or C₂-C₆alkynyl;

provided that said compound is not tert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate.

In addition, the invention features a compound of formula I or formulaI′ (preferably formula I), or a pharmaceutically acceptable salt, esteror prodrug thereof, wherein Y is N, and R′ is

and is optionally substituted with one or more R₂;

k=3, j=l, m=, n=0, 1, 2, 3, or 4, and L is absent; J is —C(O)— or—O—C(O)—; A is C₅-C₆carbocyclic or a heterocyclic comprising 5 to 6 ringatoms, and is optionally substituted with one or more R₆;

G is -E-R₅, E is —NHS(O₂)—; R₅ is C₃-C₆carbocyclic or heteroaryl, and isoptionally substituted with one or more R₇;

each R₁ and R₂ are independently selected from halogen, hydroxy, amino,—CN, —CF₃, —N₃, —NO₂, —OR₄, —SR₄, —S(O)R₄, —S(O₂)R₄, —NR₃R₄, —C(O)OR₄,—C(O)R₄, —C(O)NR_R₄, —N(R₃)C(O)R₄, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₁-C₆haloalkyl, C₂-C₆haloalkenyl, or C₂-C₆haloalkynyl;

R₃ is hydrogen; and each R₄ is independently selected from hydrogen,C₁-C₆alkyl, C₂-C₆alkenyl, or C₂-C₆alkynyl and R₆ and R₇ are as definedabove;

provided that said compound is not tert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate.

In one embodiment, R₅ is selected from cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, pyrimidinyl, furanyl,thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperidinyl,piperazinyl, or imidazolyl, each of which is optionally substituted withone or more R₇. Preferably, R₅ is cyclopropyl. A can be, for example,selected from the following groups and optionally substituted with oneor more R₆;

Representative compounds include, but are not limited to, the followingcompounds:

-   (1) tert-butyl    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;-   (2)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(isonicotinamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,    14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (3)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(2-fluorobenzamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (4)    N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide;-   (5)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (6)    N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)isoxazole-5-carboxamide;-   (7)    N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)thiazole-4-carboxamide;-   (8)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (9)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (10)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1,3-dimethyl-1H-pyrazole-4-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,    15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (11)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(3-fluorobenzamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (12) tert-butyl    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;-   (13)    N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide;-   (14)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (15)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (16)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide:-   (17)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (18) tert-butyl    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;-   (19)    N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide;-   (20)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (21)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (22)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-1,4a-carboxamide;-   (23)    (2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (24) tert-butyl    (2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;-   (25)    (2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-6-(pyrazine-2-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,    15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (26) Cyclopentyl    (2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate-   (27)    (2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(5-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a]j[1,4]diazacyclopentadecine-14a-carboxamide;-   (28)    N-((2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide;-   (29)    (2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[c]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (30)    N-((2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)thiazole-5-carboxamide;-   (31)    (2R,6S,13aS,14R,16aS,Z)—N-(cyclopropylsulfonyl)-6-(2-fluorobenzamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (32)    (2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-6-(pyridazine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (33)    (2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (34)    (2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(1-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide:-   (35)    (2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(2-hydroxy-2-methylpropanamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (36)    (2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (37) Cyclopentyl    (2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(2-fluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;-   (38) tert-Butyl    (2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(2,9-difluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[c]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;-   (39) tert-butyl    (2R,6S,13aR,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;-   (40) Cyclopentyl    (2R,6S,13aR,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;-   (41) tert-Butyl    (2R,6S,13aR,14aR,16aS)-5,16-dioxo-2-(phenanthridin-6-yloxy)-14a-(thiophen-2-ylsulfonylcarbamoyl)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;-   (42)    (2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(5-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;-   (43) Cyclopentyl    (1aR,3aS,5R,9S,16aS,Z)-1a-(cyclopropylsulfonylcarbamoyl)-5-(2-fluorophenanthridin-6-yloxy)-3,8-dioxo-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-9-ylcarbamate;-   (44) tert-butyl    (1aR,3aS,5R,9S,16aS,Z)-1a-(cyclopropylsulfonylcarbamoyl)-5-(9-fluorophenanthridin-6-yloxy)-3,8-dioxo-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-9-ylcarbamate;-   (45) tert-butyl    (1aR,3aS,5R,9S,16aS,Z)-1a-(cyclopropylsulfonylcarbamoyl)-5-(8-fluorophenanthridin-6-yloxy)-3,8-dioxo-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-9-ylcarbamate;-   (46)    (1aR,3aS,5R,9S,16aR,Z)-5-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-9-(isonicotinamido)-3,8-dioxo-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-1a-carboxamide;-   (47)    (1aR,3aS,5R,9S,16aR,Z)-5-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-9-(5-methylpyrazine-2-carboxamido)-3,8-dioxo-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-1a-carboxamide;-   (48) cyclopentyl    (2R,6S,13aR,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;-   (49) tert-butyl    (1aR,3aS,5R,9S,16aS,Z)-1a-(cyclopropylsulfonylcarbamoyl)-5-(2,9-difluorophenanthridin-6-yloxy)-3,8-dioxo-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-9-ylcarbamate;-   (50) tert-butyl    (1aR,3aS,5R,9S,16aS,Z)-1a-(cyclopropylsulfonylcarbamoyl)-5-(2,10-difluorophenanthridin-6-yloxy)-3,8-dioxo-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-9-ylcarbamate;-   (51) tert-butyl    (1aR,3aS,5R,9S,16aR,Z)-1a-(cyclopropylsulfonylcarbamoyl)-5-(3-(naphthalen-2-yl)quinoxalin-2-yloxy)-3,8-dioxo-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-9-ylcarbamate;-   (52) tert-butyl    (1aR,3aS,5R,9S,16aR,Z)-1a-(cyclopropylsulfonylcarbamoyl)-5-(3-(naphthalen-1-yl)quinoxalin-2-yloxy)-3,8-dioxo-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-9-ylcarbamate;-   (53) tert-butyl    (1aR,3aS,5R,9S,16aR,Z)-5-(3-(1H-indol-5-yl)quinoxalin-2-yloxy)-1a-(cyclopropylsulfonylcarbamoyl)-3,8-dioxo-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-9-ylcarbamate;-   (54) tert-butyl    (1aR,3aS,5R,9S,16aR,Z)-5-(3-(1H-indol-6-yl)quinoxalin-2-yloxy)-1a-(cyclopropylsulfonylcarbamoyl)-3,8-dioxo-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-9-ylcarbamate;-   (55) tert-butyl    (1aR,3aS,5R,9S,16aR,Z)-1a-(cyclopropylsulfonylcarbamoyl)-3,8-dioxo-5-(3-(quinolin-3-yl)quinoxalin-2-yloxy)-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-9-ylcarbamate;-   (56) tert-butyl    (1aR,3aS,5R,9S,16aR,Z)-5-(3-(benzo[d][,3]dioxol-5-yl)quinoxalin-2-yloxy)-1a-(cyclopropylsulfonylcarbamoyl)-3,8-dioxo-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-9-ylcarbamate;-   (57)    (1aR,3aS,5R,9S,16aR,Z)-5-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-9-(5-methylpyrazine-2-carboxamido)-3,8-dioxo-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-1a-carboxamide;    and-   (58) tert-butyl    (1aR,3aS,5R,9S,16aS,Z)-1a-(cyclopropylsulfonylcarbamoyl)-3,8-dioxo-5-(thiazolo[4,5-c]quinolin-4-yloxy)-1,1a,2,3,3a,4,5,6,8,9,10,11,12,13,14,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-9-ylcarbamate;    and-   (59) tert-Butyl    (2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(3,9-difluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate.

In another aspect, the invention provides a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula Ior I′ described herein, or the embodiments described above, or apharmaceutically acceptable salt, ester, or prodrug thereof, incombination with a pharmaceutically acceptable carrier or excipient.

According to another embodiment, the pharmaceutical compositions of thepresent invention may further contain one or more other anti-HCV agents.Examples of anti-HCV agents include, but are not limited to,α-interferon; β-interferon; pegylated interferon-α; pegylatedinterferon-lambda; ribavirin; viramidine; R-5158; nitazoxanide;amantadine; Debio-025, NIM-811; HCV polymerase inhibitors such as R7128,R1626, R4048, T-1106, PSI-7851, PF-00868554, ANA-598, IDX184, IDX102,IDX375, GS-9190, VCH-759, VCH-916, MK-3281, BCX-4678, MK-3281, VBY708,ANA598, GL59728 or GL60667; BMS-790052; BMS-791325; BMS-650032; HCVentry, helicase or internal ribosome entry site inhibitors; or other HCVreplication inhibitors such as GS-9132, ACH-1095, AP-H005, A-831, A-689,AZD2836. For further details see S. Tan, A. Pause, Y. Shi, N. Sonenberg,Hepatitis C Therapeutics: Current Status and Emerging Strategies, NatureRev. Drug Discov., 1, 867-881 (2002); WO 00/59929 (2000); WO 99/07733(1999); WO 00/09543 (2000); WO 99/50230 (1999); U.S. Pat. No. 5,861,297(1999); and US2002/0037998 (2002).

According to an additional embodiment, the pharmaceutical compositionsof the present invention may further contain another HCV proteaseinhibitor, such as telaprevir, boceprevir, ITMN-191, BI-201335, TMC-435,MK-7009, VBY-376, VX-500, VX-813, PHX-B, ACH-1625, IDX136, or IDX316.

In other embodiments, the invention provides a pharmaceuticalcomposition further comprising pegylated interferon, another anti-viral,anti-bacterial, anti-fungal or anti-cancer agent, or an immunemodulator, and/or further comprising a cytochrome P450 monooxygenaseinhibitor or a pharmaceutically acceptable salt thereof. In certainembodiments, the cytochrome P450 monooxygenase inhibitor is ritonavir.

In another aspect, the invention provides for the use of a compound ofthe invention to manufacture an agent for preventing or treating viralinfection. In another aspect, the invention provides for the use of acompound of the invention to manufacture an agent for preventing ortreating hepatitis C infection. The present invention also contemplatesthe use of a solvate (e.g., hydrate) of a compound of the invention tomanufacture pharmaceutical compositions for preventing or treatinghepatitis C infection. As used herein, “solvate” refers to the physicalassociation of a compound of the invention with one or more solventmolecule, whether organic or inorganic. This physical association oftenincludes hydrogen bonding. In certain instances, the solvate is capableof isolation, for example, when one or more solvate molecules areincorporated in the crystal lattice of the crystalline solid.

In another embodiment, the compounds or pharmaceutical compositions ofthe invention are administered with ritonavir, either simultaneously orsequentially. In certain embodiments, a compound or a pharmaceuticalcomposition of the invention is administered in the same composition asritonavir. In another embodiment, a compound or a pharmaceuticalcomposition thereof of the invention is administered in a differentcomposition than ritonavir.

According to yet another embodiment, the pharmaceutical compositions ofthe present invention may further comprise inhibitor(s) of other targetsin the HCV life cycle, including, but not limited to, helicase,polymerase, metalloprotease, CD81, NS5A, cyclophilin, and internalribosome entry site (IRES).

In one aspect, the invention provides a method of treating a viralinfection in a subject, comprising administering to the subject atherapeutically effective amount of a compound of formula I or I′described herein, or a pharmaceutically acceptable salt, ester orprodrug thereof, or a pharmaceutical composition comprising the same.

According to a further embodiment, the present invention includesmethods of treating hepatitis C infections in a subject in need of suchtreatment by administering to said subject an anti-HCV virally effectiveamount or an inhibitory amount of the compounds or pharmaceuticalcompositions of the present invention.

According to another embodiment, the present invention includes methodsof treating hepatitis C infections in a subject in need of suchtreatment by administering to said subject a compound or apharmaceutical composition of the present invention. The methods canfurther include administration of an additional therapeutic agent,including another antiviral agent or an anti-HCV agent as describedhereinabove. The additional agent can be co-administered (such asconcurrently administered or sequentially administered) with a compound(a pharmaceutically acceptable salt, ester or prodrug thereof) or apharmaceutical composition of the present invention. The additionalagent(s) and a compound (or a pharmaceutically acceptable salt, ester orprodrug thereof) of the present invention can be formulated in the samecomposition, or in different compositions but co-administeredconcurrently or sequentially. The methods herein can further include thestep of identifying that the subject is in need of treatment forhepatitis C infection. The identification can be by subjective (e.g.,health care provider determination) or objective (e.g., diagnostic test)means.

In one aspect, the invention provides a method of inhibiting thereplication of hepatitis C virus, the method comprising contacting ahepatitis C virus with an effective amount of a compound orpharmaceutical composition of the invention.

In another embodiment, the invention provides a method as describedabove, further comprising administering an additional anti-hepatitis Cvirus agent. Examples of anti-hepatitis C virus agents include, but arenot limited to, α-interferon; β-interferon; pegylated interferon-α;pegylated interferon-lambda; ribavirin; viramidine; R-5158;nitazoxanide; amantadine; Debio-025, NIM-811; HCV polymerase inhibitorssuch as R7128, R1626, R4048, T-1106, PSI-7851, PF-00868554, ANA-598,IDX184, IDX102, IDX375, GS-9190, VCH-759, VCH-916, MK-3281, BCX-4678,MK-3281, VBY708, ANA598, GL59728 or GL60667; BMS-790052; BMS-791325;BMS-650032; HCV entry, helicase or internal ribosome entry siteinhibitors; or other HCV replication inhibitors such as GS-9132,ACH-1095, AP-H005, A-831, A-689, AZD2836. For further details see S.Tan, A. Pause, Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: CurrentStatus and Emerging Strategies, Nature Rev. Drug Discov., 1, 867-881(2002); WO 00/59929 (2000); WO 99/07733 (1999); WO 00/09543 (2000); WO99/50230 (1999); U.S. Pat. No. 5,861,297 (1999); and US2002/0037998(2002). Preferably, a compound or a pharmaceutical composition of thepresent invention is co-administered with, or used in combination with,pegylated interferon (e.g., pegylated interferon alpha-2a or 2b) andribavirin. Ritonavir or another cytochrome P450 monooxygenase inhibitorcan also be used to enhance the pharmacokinetics of the compound of thepresent invention. The patient being treated is preferably infected withHCV genotype-1 (e.g., genotype 1a or 1b). Patients infected with otherHCV genotypes, such as genotypes 2, 3, 4, 5 or 6, can also be treatedwith a compound or a pharmaceutical composition of the presentinvention.

In another embodiment, the invention provides a method as describedabove, further comprising administering another HCV protease inhibitor,an HCV polymerase inhibitor, an HCV helicase inhibitor, or an internalribosome entry site (IRES) inhibitor, such as telaprevir, boceprevir,ITMN-191, BI-201335, TMC-435, MK-7009, VBY-376, VX-500, VX-813, PHX-B,ACH-1625, IDX136, IDX316, pegylated interferon, another anti-viral,anti-bacterial, anti-fungal or anti-cancer agent, or an immunemodulator, and/or further comprising a cytochrome P450 monooxygenaseinhibitor or a pharmaceutically acceptable salt thereof. In certainembodiments, the cytochrome P450 monooxygenase inhibitor is ritonavir.

An additional embodiment of the present invention includes methods oftreating biological samples by contacting the biological samples withthe compounds of the present invention.

Yet another aspect of the present invention is a process of making anyof the compounds delineated herein employing any of the synthetic meansdelineated herein.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.The number of carbon atoms in a hydrocarbyl substituent can be indicatedby the prefix “C_(x)-C_(y),” where x is the minimum and y is the maximumnumber of carbon atoms in the substituent.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogenradicals. For example, “haloalkyl” means an alkyl substituent wherein atleast one hydrogen radical is replaced with a halogen radical.

If a linking element in a depicted structure is “absent”, then the leftelement in the depicted structure is directly linked to the rightelement in the depicted structure. For example, if a chemical structureis depicted as X-L-Y wherein L is absent, then the chemical structure isX—Y.

The term “alkyl” as used herein, refers to a saturated, straight- orbranched-chain hydrocarbon radical typically containing from 1 to 20carbon atoms. For example, “C₁-C₆ alkyl” or “C₁-C₈alkyl” contains fromone to six, or from one to eight, carbon atoms, respectively.

Examples of alkyl radicals include, but are not limited to, methyl,ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl,heptyl, octyl radicals and the like.

The term “alkenyl” as used herein, denotes a straight- or branched-chainhydrocarbon radical containing one or more double bonds and typicallyfrom 2 to 20 carbon atoms. For example, “C₂-C₆ alkenyl” or“C₂-C₈alkenyl” contains from two to six, or from two to eight carbonatoms, respectively. Alkenyl groups include, but are not limited to, forexample, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl,octenyl and the like.

The term “alkynyl” as used herein, denotes a straight- or branched-chainhydrocarbon radical containing one or more triple bonds and typicallyfrom 2 to 20 carbon atoms. For example, “C₂-C₆ alkynyl” or“C₂-C₈alkynyl” contains from two to six, or from two to eight, carbonatoms, respectively. Representative alkynyl groups include, but are notlimited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl,octynyl and the like.

The term “alkylene” refers to a divalent group derived from a straightor branched saturated hydrocarbyl chain typically containing from 1 to20 carbon atoms, more typically from 1 to 8 carbon atoms, and even moretypically from 1 to 6 carbon atoms. Representative examples of alkyleneinclude, but are not limited to, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkenylene” refers to a divalent unsaturated hydrocarbyl groupwhich may be linear or branched and which has at least one carbon-carbondouble bond. An alkenylene group typically contains 2 to 20 carbonatoms, more typically from 2 to 8 carbon atoms, and even more typicallyfrom 2 to 6 carbon atoms. Non-limiting examples of alkenylene groupsinclude —C(H)═C(H)—, —C(H)═C(H)—CH—, —C(H)═(H)—CH₂—CH₂—,—CH₂—C(H)═C(H)—CH₂—, —C(H)═C(H)—CH(CH₃)—, and —CH—C(H)═C(H)—CH(CH₂CH₃)—.

The term “alkynylene” refers to a divalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one carbon-carbontriple bond. Representative alkynylene groups include, by way ofexample, —C≡C—, —C≡C—CH₂—, —C≡C—CH₂—CH₂—, —CH₂—C≡C—CH₂—, —C≡C—CH(CH₃)—,and —CH₂—C≡C—CH(CH₂CH₃)—.

The term “cycloalkyl” denotes a monovalent group derived from amonocyclic or polycyclic saturated carbocyclic ring compound. Examplesof cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyland the like.

The terms “carbocycle” or “carbocyclic” or “carbocyclyl” refer to asaturated (e.g., “cycloalkyl”), partially saturated (e.g.,“cycloalkenyl” or “cycloalkynyl”) or completely unsaturated (e.g.,“aryl”) ring system containing zero heteroatom ring atom and typicallyfrom 3 to 18 carbon ring atoms. A carbocyclyl may be, withoutlimitation, a single ring, or two or more fused rings, or bridged orspiro rings. A carbocyclyl may contain, for example, from 3 to 14 ringmembers (i.e., C₃-C₁₄carbocyclyl, such as C₃-C₁₄cycloalkyl), from 3 to10 ring members (i.e., C₃-C₁₀carbocyclyl, such as C₃-C₁₀cycloalkyl),from 3 to 8 ring members (i.e., C₃-C₆carbocyclyl, such asC₃-C₈cycloalkyl), or from 3 to 6 ring members (i.e., C₃-C₆carbocyclyl,such as C₃-C₆cycloalkyl). A substituted carbocyclyl may have either cisor trans geometry. Representative examples of carbocyclyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl,cyclohexadienyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl,cyclohexenyl, phenyl, naphthyl, fluorenyl, indanyl,1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl, bicyclodecanyl,anthracenyl, phenanthrene, benzonaphthenyl (also known as “phenalenyl”),decalinyl, and norpinanyl and the like. A carbocyclyl group can beattached to the parent molecular moiety through any substitutable carbonatom of the group.

The term “aryl” refers to an aromatic carbocyclyl containing from 6 to14 carbon ring atoms. Non-limiting examples of aryls include phenyl,naphthalenyl, anthracenyl, and indenyl and the like. An aryl group canbe connected to the parent molecular moiety through any substitutablecarbon atom of the group.

The term “aralkyl” or “arylalkyl” refers to an alkyl residue attached toan aryl ring. Examples of aralkyl include, but are not limited to,benzyl, phenethyl and the like.

The term “heteroaryl” means an aromatic heterocyclyl typicallycontaining from 5 to 18 ring atoms. A heteroaryl may be a single ring,or two or more fused rings. Non-limiting examples of five-memberedheteroaryls include imidazolyl; furanyl; thiophenyl (or thienyl orthiofuranyl); pyrazolyl; oxazolyl; isoxazolyl; thiazolyl; 1,2,3-,1,2,4-, 1,2,5-, and 1,3,4-oxadiazolyl; and isothiazolyl. Non-limitingexamples of six-membered heteroaryls include pyridinyl; pyrazinyl;pyrimidinyl; pyridazinyl; and 1,3,5-, 1,2,4-, and 1,2,3-triazinyl.Non-limiting examples of 6/5-membered fused ring heteroaryls includebenzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl,purinyl, and anthranilyl. Non-limiting examples of 6/6-membered fusedring heteroaryls include quinolinyl; isoquinolinyl; and benzoxazinyl(including cinnolinyl and quinazolinyl).

The term “heteroaralkyl” or “heteroarylalkyl” refers to an alkyl residueattached to a heteroaryl ring. Examples include, but are not limited to,pyridinylmethyl, pyrimidinylmethyl and the like.

The term “heterocycloalkyl” refers to a non-aromatic 3-, 4-, 5-, 6- or7-membered ring or a bi- or tri-cyclic group fused system, where (i)each ring contains between one and three heteroatoms independentlyselected from oxygen, sulfur and nitrogen, (ii) each 5-membered ring has0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds,(iii) the nitrogen and sulfur heteroatoms may optionally be oxidized,(iv) the nitrogen heteroatom may optionally be quaternized, and (iv) anyof the above rings may be fused to a benzene ring. Representativeheterocycloalkyl groups include, but are not limited to, [1,3]dioxolane,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl and the like.

The terms “heterocyclic” or “heterocyclo” or “heterocyclyl” refer to asaturated (e.g., “heterocycloalkyl”), partially unsaturated (e.g.,“heterocycloalkenyl” or “heterocycloalkynyl”) or completely unsaturated(e.g., “heteroaryl”) ring system typically containing from 3 to 18 ringatoms, where at least one of the ring atoms is a heteroatom (i.e.,nitrogen, oxygen or sulfur), with the remaining ring atoms beingindependently selected from the group consisting of carbon, nitrogen,oxygen and sulfur. A heterocyclyl group can be linked to the parentmolecular moiety via any substitutable carbon or nitrogen atom in thegroup, provided that a stable molecule results. A heterocyclyl may be,without limitation, a single ring, which typically contains from 3 to 14ring atoms, from 3 to 8 ring atoms, from 3 to 6 ring atoms, or from 5 to6 ring atoms. Non-limiting examples of single-ring heterocyclyls includefuranyl, dihydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl,pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl,pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl,oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl,isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl,oxathiazolyl, oxadiazoly, pyranyl, dihydropyranyl, pyridinyl,piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl,triazinyl, isoxazinyl, oxazolidinyl, isoxazolidinyl, oxathiazinyl,oxadiazinyl, morpholinyl, azepinyl, oxepinyl, thiepinyl, or diazepinyl.A heterocyclyl may also include, without limitation, two or more ringsfused together, such as, for example, naphthyridinyl,thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, orpyridopyrimidinyl. A heterocyclyl may comprise one or more sulfur atomsas ring members, and in some cases, the sulfur atom(s) is oxidized to SOor SO₂. The nitrogen heteroatom(s) in a heterocyclyl may or may not bequaternized, and may or may not be oxidized to N-oxide. In addition, thenitrogen heteroatom(s) may or may not be N-protected.

The terms “optionally substituted”, “optionally substituted alkyl,”“optionally substituted “optionally substituted alkenyl,” “optionallysubstituted alkynyl”, “optionally substituted carbocyclic,” “optionallysubstituted aryl”, “optionally substituted heteroaryl,” “optionallysubstituted heterocyclic,” and any other optionally substituted group asused herein, refer to groups that are substituted or unsubstituted byindependent replacement of one, two, or three or more of the hydrogenatoms thereon with substituents including, but not limited to:

—F, —Cl, —Br, —I,

—OH, protected hydroxy, alkoxy, oxo, thiooxo,

—NO₂, —CN, CF₃, N₃,

—NH₂, protected amino, —NH alkyl, —NH alkenyl, —NH alkynyl, —NHcycloalkyl, —NH— aryl, —NH-heteroaryl, —NH-heterocyclic, -dialkylamino,-diarylamino, -diheteroarylamino,

—O— alkyl, —O— alkenyl, —O— alkynyl, —O— cycloalkyl, —O-aryl,—O-heteroaryl, —O— heterocyclic,

—C(O)— alkyl, —C(O)— alkenyl, —C(O)— alkynyl, —C(O)— cycloalkyl,—C(O)-aryl, —C(O)— heteroaryl, —C(O)— heterocycloalkyl,

—CONH₂, —CONH— alkyl, —CONH— alkenyl, —CONH— alkynyl, —CONH— cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl,

—OCO₂— alkyl, —OCO₂— alkenyl, —OCO₂— alkynyl, —OCO₂— cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—alkyl, —OCONH— alkenyl, —OCONH— alkynyl, —OCONH— cycloalkyl, —OCONH—aryl, —OCONH— heteroaryl, —OCONH— heterocycloalkyl,

—NHC(O)— alkyl, —NHC(O)— alkenyl, —NHC(O)— alkynyl, —NHC(O)— cycloalkyl,—NHC(O)-aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocycloalkyl, —NHCO₂—alkyl, —NHCO₂-alkenyl, —NHCO₂— alkynyl, —NHCO₂-cycloalkyl, —NHCO₂— aryl,—NHCO₂— heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂, —NHC(O)NH—alkyl, —NHC(O)NH— alkenyl, —NHC(O)NH— alkenyl, —NHC(O)NH— cycloalkyl,—NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, —NHC(O)NH— heterocycloalkyl,NHC(S)NH₂, —NHC(S)NH— alkyl, —NHC(S)NH— alkenyl, —NHC(S)NH— alkynyl,—NHC(S)NH— cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(S)NH—heterocycloalkyl, —NHC(NH)NH₂, —NHC(NH)NH— alkyl, —NHC(NH)NH— alkenyl,—NHC(NH)NH— alkenyl, —NHC(NH)NH— cycloalkyl, —NHC(NH)NH-aryl,—NHC(NH)NH— heteroaryl, —NHC(NH)NH-heterocycloalkyl, —NHC(NH)— alkyl,—NHC(NH)— alkenyl, —NHC(NH)— alkenyl, —NHC(NH)— cycloalkyl,—NHC(NH)-aryl, —NHC(NH)-heteroaryl, —NHC(NH)-heterocycloalkyl, —C(NH)NH—alkyl, —C(NH)NH— alkenyl, —C(NH)NH— alkynyl, —C(NH)NH— cycloalkyl,—C(NH)NH-aryl, —C(NH)NH-heteroaryl, —C(NH)NH-heterocycloalkyl,

—S(O)— alkyl, —S(O)— alkenyl, —S(O)— alkynyl, —S(O)— cycloalkyl,—S(O)-aryl, —S(O)— heteroaryl, —S(O)-heterocycloalkyl —SO₂NH₂, —SO₂NH—alkyl, —SO₂NH— alkenyl, —SO₂NH— alkynyl, —SO₂NH— cycloalkyl, —SO₂NH—aryl, —SO₂NH— heteroaryl, —SO₂NH— heterocycloalkyl,

—NHSO₂— alkyl, —NHSO₂— alkenyl, —NHSO₂— alkynyl, —NHSO₂— cycloalkyl,—NHSO₂-aryl, —NHSO₂-heteroaryl, —NHSO₂-heterocycloalkyl,

—CH₂NH₂, —CH₂SO₂CH₃, -alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl,-carbocyclic, -heterocyclic, polyalkoxyalkyl, polyalkoxy,-methoxymethoxy, -methoxyethoxy, —SH, —S— alkyl, —S— alkenyl, —S—alkynyl, —S— cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl.

It is understood that the aryls, heteroaryls, carbocyclics,heterocyclics, alkyls, and the like can be further substituted.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be either a patient or a healthy human.

The term “hydroxy activating group”, as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxy group sothat it will depart during synthetic procedures such as in asubstitution or elimination reactions. Examples of hydroxy activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “leaving group,” or “LG”, as used herein, refers to any groupthat leaves in the course of a chemical reaction involving the group andincludes but is not limited to halogen, brosylate, mesylate, tosylate,triflate, p-nitrobenzoate, phosphonate groups, for example.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxy groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of hydroxy protecting groups include benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl(trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-trichloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxy protecting groups for the present invention are acetyl(Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl (TMS or—Si(CH₃)₃).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “alkylamino” refers to a group having the structure—N(R_(a)R_(b)), where R_(a) and R_(b) are independent H or alkyl.

The term “acyl” includes residues derived from acids, including but notlimited to carboxylic acids, carbamic acids, carbonic acids, sulfonicacids, and phosphorous acids. Examples include aliphatic carbonyls,aromatic carbonyls, aliphatic sulfonyls, aromatic sulfinyls, aliphaticsulfinyls, aromatic phosphates and aliphatic phosphates. Examples ofaliphatic carbonyls include, but are not limited to, acetyl, propionyl,2-fluoroacetyl, butyryl, 2-hydroxy acetyl, and the like.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts, or saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, or magnesium salts, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms,sulfonate and aryl sulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present inventionwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present invention. “Prodrug”, as used hereinmeans a compound which is convertible in vivo by metabolic means (e.g.by hydrolysis) to afford any compound delineated by the formulae of theinstant invention. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988);Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems,American Chemical Society (1975); and Bernard Testa & Joachim Mayer,“Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry AndEnzymology,” John Wiley and Sons, Ltd. (2002).

This invention also encompasses pharmaceutical compositions containing,and methods of treating viral infections through administering,pharmaceutically acceptable prodrugs of compounds of the invention. Forexample, compounds of the invention having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the invention. The amino acidresidues include but are not limited to the 20 naturally occurring aminoacids commonly designated by three letter symbols and also includes4-hydroxyproline, hydroxysine, demosine, isodemosine, 3-methylhistidine,norvalin, beta-alanine, gamma-aminobutyric acid, citrulline,homocysteine, homoserine, ornithine and methionine sulfone. Additionaltypes of prodrugs are also encompassed. For instance, free carboxylgroups can be derivatized as amides or alkyl esters. Free hydroxy groupsmay be derivatized using groups including but not limited tohemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Thepharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), buccally, or as an oral or nasal spray.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups,and elixirs. In addition to the active compounds, the liquid dosageforms may contain inert diluents commonly used in the art such as, forexample, water, alcohol or other solvents, solubilizing agents andemulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, polysorbate, dimethylformamide, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor, and sesameoils), mono- or di-glycerides, glycerol, tetrahydrofurfuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof. Besides inert diluents, the oral compositions can also includeadjuvants such as wetting agents, emulsifying and suspending agents,antioxidants, sweetening, flavoring, and perfuming agents. The liquiddosage form can also be encapsulated in a gelatin capsule, wherein acompound of the present invention can be dissolved in a pharmaceuticallyacceptable carrier containing, for example, one or more solubilizatingagents (e.g., polysorbate 80 and mono and diglycerides), and othersuitable excipients (e.g., an antioxidants such as ascorbyl palmitate,or a sweetening or flavoring agent).

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Immediate release forms are also contemplated by the presentinvention.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings, release controlling coatings and other coatings well known inthe pharmaceutical formulating art. In such solid dosage forms theactive compound may be admixed with at least one inert diluent such assucrose, lactose or starch.

Such dosage forms may also comprise, as is normal practice, additionalsubstances other than inert diluents, e.g., tableting lubricants andother tableting aids such a magnesium stearate and microcrystallinecellulose. In the case of capsules, tablets and pills, the dosage formsmay also comprise buffering agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

According to the methods of treatment of the present invention, viralinfections are treated or prevented in a subject, such as a human oranother animal, by administering to the subject a therapeuticallyeffective amount of a compound of the invention (or a pharmaceuticallyacceptable salt, ester or prodrug thereof), in such amounts and for suchtime as is necessary to achieve the desired result. The term“therapeutically effective amount” of a compound of the invention, asused herein, means a sufficient amount of the compound so as to decreasethe viral load in a subject and/or decrease the subject's HCV symptoms.As is well understood in the medical arts a therapeutically effectiveamount of a compound of this invention will be at a reasonablebenefit/risk ratio applicable to any medical treatment.

Antiviral Activity

An inhibitory amount or dose of the compounds of the present inventionmay range from about 0.1 mg/Kg to about 500 mg/Kg, alternatively fromabout 1 to about 50 mg/Kg. Inhibitory amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

According to the methods of treatment of the present invention, viralinfections are treated or prevented in a subject such as a human orlower mammal by administering to the subject an anti-hepatitis C virallyeffective amount or an inhibitory amount of a compound of the presentinvention, in such amounts and for such time as is necessary to achievethe desired result. An additional method of the present invention is thetreatment of biological samples with an inhibitory amount of a compoundof composition of the present invention in such amounts and for suchtime as is necessary to achieve the desired result.

The term “anti-hepatitis C virally effective amount” of a compound ofthe invention, as used herein, means a sufficient amount of the compoundso as to decrease the viral load in a biological sample or in a subject.As well understood in the medical arts, an anti-hepatitis C virallyeffective amount of a compound of this invention will be at a reasonablebenefit/risk ratio applicable to any medical treatment.

The term “inhibitory amount” of a compound of the present inventionmeans a sufficient amount to decrease the hepatitis C viral load in abiological sample or a subject. It is understood that when saidinhibitory amount of a compound of the present invention is administeredto a subject it will be at a reasonable benefit/risk ratio applicable toany medical treatment as determined by a physician. The term “biologicalsample(s),” as used herein, means a substance of biological originintended for administration to a subject. Examples of biological samplesinclude, but are not limited to, blood and components thereof such asplasma, platelets, subpopulations of blood cells and the like; organssuch as kidney, liver, heart, lung, and the like: sperm and ova; bonemarrow and components thereof; or stem cells. Thus, another embodimentof the present invention is a method of treating a biological sample bycontacting said biological sample with an inhibitory amount of acompound or pharmaceutical composition of the present invention.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific inhibitory dose for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder, the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

The total daily inhibitory dose of the compounds of this inventionadministered to a subject in single or in divided doses can be inamounts, for example, from 0.01 to 50 mg/kg body weight or more usuallyfrom 0.1 to 25 mg/kg body weight. Single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose. In oneembodiment, treatment regimens according to the present inventioncomprise administration to a patient in need of such treatment fromabout 10 mg to about 1000 mg of the compound(s) of this invention perday in single or multiple doses. In another embodiment, the treatmentregimen comprises administration to a patient in need of such treatmentfrom about 25 mg to about 6000 mg of a compound(s) of this invention perday in single or multiple doses, either with or without a cytochromeP450 monooxygenase inhibitor such as ritonavir. The suitable daily dosefor the co-administered cytochrome P450 monooxygenase inhibitor (e.g.,ritonavir) can range, without limitation, from 10 to 200 mg. Preferably,a compound(s) of the present invention, or a combination of acompound(s) of the invention and ritonavir, is administered once dailyor twice daily to achieve the desired daily dose amount. For instance,when used without ritonavir, a compound of the present invention can beadministered to a patient twice a day with a total daily dose of 4000,4200, 4400, 4600, 4800 or 5000 mg. For another instance, when used incombination with ritonavir, a compound of the present invention can beadministered to a patient once or twice a day with a total daily dose of200, 400, 600 or 800 mg, where the amount of ritonavir can be 25, 50 or100 mg per administration.

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared.

Definitions of variables in the structures in the schemes herein arecommensurate with those of corresponding positions in the formulaedelineated herein.

Scheme 1 describes the synthesis of various compounds of the invention.The starting material was displaced at the leaving groups by reactionwith a nucleophile to provide a nucleophile substituted macrocycle. Basehydrolysis of the ester to the acid was followed by coupling of asulfonamide derivative. The protected nitrogen was then deprotected andsubstituted with another group.

In one aspect, the invention provides a method of producing a compoundof formula I, comprising the step of reacting a compound of formula II:

wherein,

J is absent, optionally substituted alkylene, optionally substitutedalkenylene, optionally substituted alkynylene, —C(O)—, —O—C(O)—,—N(R₃)—C(O)—, —C(S)—, —C(═NR₄)—, —S(O)—, —S(O_(p))—, or —N(R₃)—;

A is optionally substituted alkyl, optionally substituted alkenyl, oroptionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl,optionally substituted arylalkyl, optionally substituted alkoxy,optionally substituted heteroaryl, optionally substituted heterocyclic,or optionally substituted carbocyclic;

G is -E-R5;

-   -   wherein E is absent; optionally substituted alkylene, optionally        substituted alkenylene, optionally substituted alkynylene, each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        or —O—, —S—, —N(R₃)—, —N(R₃)S(O_(p))—, —N(R₃)C(O)—, —N(R₃)        C(O)S(O_(p))—, —OS(O_(p))—, —C(O)S(O_(p))—, or        —C(O)N(R₃)S(O_(p))—;    -   p is 0, 1, or 2;    -   R₅ is H; optionally substituted alkyl, optionally substituted        alkenyl, or optionally substituted alkynyl, each containing 0,        1, 2, or 3 heteroatoms selected from O, S, or N;    -   optionally substituted carbocyclic, optionally substituted        heterocyclic, optionally substituted aryl, or optionally        substituted heteroaryl;

Each R₃ and R₄ is independently selected at each occurrence from thefollowing: optionally substituted alkyl, optionally substituted alkenylor optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

L is absent or is selected from optionally substituted alkylene,optionally substituted alkenylene or optionally substituted alkynylene,each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;

j=0, 1, 2, 3, or 4;

k=0, 1, 2, or 3;

m=0, 1, or 2;

n is 0, 1, 2, 3, or 4; and

denotes a carbon-carbon single or double bond; and

LG is a leaving group;

with a compound of formula III:

wherein:

Each R₁ is independently selected from

-   -   (i) halogen, hydroxy, amino, —CN, —CF₃, —N₃, —NO₂, —OR₄, —SR₄,        —SOR₄, —SO₂R₄, —N(R₃)S(O)₂—R₄, —N(R₃)(SO₂)NR₃R₄, —NR₃R₄,        —C(O)OR₄, —C(O)R₄, —C(O)NR₃R₄, or —N(R₃)C(O)R₄;    -   (ii) optionally substituted aryl;    -   (iii) optionally substituted heteroaryl;    -   (iv) optionally substituted heterocyclic;    -   (v) optionally substituted carbocyclic; or    -   (vi) optionally substituted alkyl, optionally substituted        alkenyl, or optionally substituted alkynyl, each containing 0,        1, 2, or 3 heteroatoms selected from O, S, or N;

R₃ and R₄ are each independently selected at each occurrence from thefollowing: optionally substituted alkyl, optionally substituted alkenylor optionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen;

Y is N or C(R″);

wherein if Y is N, then R′ is optionally substituted heterocyclic,optionally substituted heteroaryl, optionally substituted aryl oroptionally substituted carbocyclic, and comprises two or more fusedrings, and wherein R′ is not or

further provided that said compound is not tert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;

wherein if Y is —C(R″)—, then R′ and R″ taken together with the carbonatoms to which they are attached form an aryl or heteroaryl ring, eachsaid ring is optionally substituted;

wherein A, R₁, R′ and/or R″ can be taken together to form a ring; tothereby produce a compound of formula I or I′.

A compound of formula I can also be prepared according to the processdepicted in Scheme 2, wherein A, J, L, G, Y, R′ R₁, R₃, n, m, j, and kare defined hereinabove, and

and wherein Q is halogen or a leaving group, PG and PG_(N) are eachindependently an amino protecting group, and PG_(C) is a carboxylic acidprotecting group. Compound (b) can be prepared by reacting

with a halogenation agent such as POCl₃. Non-limiting examples of aminoprotecting group include C₁-C₆alkoxycarbonyl (e.g., tert-butoxycarbonylor Boc), carboxybenzyl, p-methoxybenzyl carbonyl,9-fluorenylmethyloxycarbonyl, benzyl, p-methoxybenzyl,3,4-dimethoxybenzyl, p-methoxyphenyl, benzoyl, or tosyl or othersuitable sulfonamides. Non-limiting examples of carboxylic acidprotecting group include C₁-C₆alkyl (e.g., tert-butyl, methyl or ethyl),benzyl, or silyl, all of which protect carboxylic acid moieties in theform of esters.

In step 1, compound (a) reacts with compound (b) to form compound (c),where the reaction can be conducted, as a non-limiting example, in thepresence of sodium tert-butoxide or potassium tert-butoxide. Preferably,the reaction is conducted in the absence of lanthanum chloride. Alsopreferably, the yield of this reaction is at least 50%. More preferably,the yield of the reaction is at least 60%, 70%, or 80%. Highlypreferably, the yield of the reaction is at least 90% or 95%. PreferredPG is C₁-C₆alkoxycarbonyl, such as tert-butoxycarbonyl or Boc.

Compound (c) can then be reacted with compound (d), or a salt thereofsuch as TsOH salt, to form compound (e) (step 2), followed byde-protection of the amino group to create compound (f) or a saltthereof (e.g., HCl salt) (step 3). Preferred PG_(C) includes, but is notlimited to, C₁-C₆alkyl such as ethyl. Compound (f) can then be reactedwith compound (g) to form compound (h) (step 4), which is subsequentlyamino-protected to form compound (1) (step 5) and then subjected toring-closing metathesis to form compound (j) (step 6). Preferred PG_(N)includes, but is not limited to, C₁-C₆alkoxycarbonyl, such astert-butoxycarbonyl or Boc. General processes for ring-closingmetathesis (RCM) are well known in the art. Preferred processes involvethe use of transition metal catalysts, such as those described in U.S.Pat. No. 6,921,753 and U.S. Patent Application Publication No.20070043180. Non-limiting examples of suitable catalysts include ZhanCatalyst-1B (

where Mes is 2,4,6-trimethylphenyl; also known as Zhan-B) and ZhanCatalyst-1C (

where Cy is cyclohexyl), both of which are commercially available fromZannan Pharma, Ltd. (Shanghai, China). De-protection of the amino moietyin compound (j) leads to compound (k) (or its free-base) (step 7). Incertain cases, compound (h) can directly undergo the ring-closingmetathesis reaction to make compound (k) (or its free-base), without theamino protecting and de-protecting steps.

The carboxylic acid moiety in compound (k) can then be deprotected toform compound (l) (step 8), which reacts with compound (m) to formcompound (n) (step 9). G in compound (m) is defined as -E-R₅, wherein Eand R₅ are defined hereinabove.

A compound of formula I′, as described herein, can be similarly preparedaccording to Scheme 2.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers. Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Theconfiguration of any carbon-carbon double bond appearing herein isselected for convenience only and is not intended to designate aparticular configuration unless the text so states; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be cis, trans, or amixture of the two in any proportion.

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formulae herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. In addition, the solvents, temperatures, reaction durations,etc. delineated herein are for purposes of illustration only and one ofordinary skill in the art will recognize that variation of the reactionconditions can produce the desired bridged macrocyclic products of thepresent invention. Synthetic chemistry transformations and protectinggroup methodologies (protection and deprotection) useful in synthesizingthe compounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds of this invention may be modified by appending variousfunctionalities via any synthetic means delineated herein to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The recitation of a listing of chemical groups in any definition of avariable herein includes definitions of that variable as any singlegroup or combination of listed groups. The recitation of an embodimentfor a variable herein includes that embodiment as any single embodimentor in combination with any other embodiments or portions thereof.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not to limit the scope of the invention. Thefollowing examples can be prepared according to either Scheme 1 orScheme 2 as described above. Various changes and modifications to thedisclosed embodiments will be apparent to those skilled in the art andsuch changes and modifications including, without limitation, thoserelating to the chemical structures, substituents, derivatives,formulations and/or methods of the invention may be made withoutdeparting from the spirit of the invention and the scope of the appendedclaims.

Example 1 tert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamateExample 1a (2S,6S,13aS,14aR,16aS,Z)-ethyl2-(4-bromophenylsulfonyloxy)-6-(tert-butoxycarbonylamino)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate

A solution of (2S,6S,13aS,14aR,16aS,Z)-ethyl6-(tert-butoxycarbonylamino)-2-hydroxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylateand DABCO in toluene was stirred at room temperature (rt). To thissolution was added a solution of 4-bromobenzene-1-sulfonyl chloride intoluene. After the addition was complete the reaction mixture wasquenched with 10% aqueous sodium carbonate and the mixture stirred for15 min. Tetrahydrofuran was added and the mixture was washed with 0.5 MHCl, water, and then saturated aqueous sodium chloride. The organiclayer was dried over anhydrous magnesium sulfate, filtered, andevaporated under reduced pressure and dried to provide the titlecompound.

Example 1b (2R,6S,13aR,14aR,16aS,Z)-ethyl6-(tert-butoxycarbonylamino)-2-(3-chloroquinoxalin-2-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][,4]diazacyclopentadecine-14a-carboxylate(1b)

To a solution of compound 1a (15.0 g, 21.0 mmol) in NMP (55 ml) wasadded 3-chloroquinoxalin-2-ol (4.56 g, 25.3 mmol) followed by Cs₂CO₃(17.1 g, 52.6 mmol). The resulting mixture was heated to 70° C. for 18hours. The reaction mixture was cooled to room temperature, and thenpartitioned between ethyl acetate (300 ml) and 1 N HCl (100 ml). Theorganic layer was separated, washed with brine (100 mil), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure toobtain the crude product as a solid. The solid was purified by columnchromatography on silica gel (EtOAc-hexane gradient) to obtain the titlecompound as a solid (6.2 g., 45% yield); MS (ESI): m/z=656.3 [M+H]

Example 1c (2R,6S,13aR,14aR,16aS,Z)-ethyl6-(tert-butoxycarbonylamino)-5,16-dioxo-2-(3-phenylquinoxalin-2-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate(1c)

To a microwave vessel was added the product from 1b (700 mg. 1.07mmole), 2-(tributylstannyl)benzo[d]thiazole (905 mg., 2.13 mmole),palladium-tetrakis(triphenylphosphine) (113 mg., 0.11 mmole) and dioxane(5 ml.). The vessel was evacuated and nitrogen introduced, which wasrepeated twice. The mixture was reacted in a microwave reactor at 110degrees C. for 1 hr. The reaction was diluted with MeCN and washed 3times with hexane. The MeCN layer was evaporated and purified by columnchromatography on silica gel (CHCl₃-EtOAc gradient) to obtain the titlecompound (692 mg., 86% yield). MS (ESI): m/z=755.2 [M+H].

Example 1d(2R,6S,13aR,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-6-(tert-butoxycarbonylamino)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylicacid (1d)

To a solution of the product of Example 1c (692 mg, 0.95 mmol) intetrahydrofuran (5 mil)/ethanol (2.5 ml)/water (2.5 ml.) was addedlithium hydroxide monohydrate (154 mg., 3.7 mmole). The resultingmixture was heated to 50° C. for one hour and cooled to roomtemperature.

The organic solvents were mostly removed under reduced pressure, EtOAc(100 ml.) was added and then washed with 1 N HCl (30 ml.). The organiclayer was separated, washed with brine (20 ml), dried over anhydrousMgSO₄, and concentrated under reduced pressure to afford 666 mg ofproduct 1d.

Example 1f

To a solution of product of Example 1d (666 mg, 0.92 mmol) in1,2-dichloroethane (9 ml) was added 1,1′-carbonyldiimidazole (246 mg,1.52 mmol). The reaction mixture was stirred at 40 degrees C. for 2hours. To the above solution was then added the cyclopropanesulfonamide(184 mg, 1.52 mmol) followed by DBU (0.23 ml, 1.52 mmol). The resultingmixture was stirred at 40 degrees C. for 1 hour. The reaction mixturewas diluted with EtOAc (100 ml) and washed with 1 N HCl (20 ml.) thensaturated sodium chloride (20 ml). The organic layer was separated,dried over anhydrous MgSO₄, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (CHCl₃/EtOAc gradient) to obtain the title compound (322 mg, 38%yield). MS (ESI): m/z=830.0 [M+H].

Example 2(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(isonicotinamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamideExample 2a(2R,6S,13aS,14aR,16aS,Z)-6-amino-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

To a suspension of the product of Example 1 (320 mg, 0.39 mmol) in EtOAc(3 mL) was added a 4 M solution of HCl in dioxane (1.9 mL, 7.7 mmol).The reaction mixture was stirred at room temperature for 20 h. Thesolvent was evaporated under reduced pressure and the resulting soliddried under vacuum to provide(2R,6S,13aR,14aR,16aS,Z)-6-amino-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide,Hydrochloric Acid (295 mg, quant. yield).

Example 2b

To a solution of Example 2a (28 mg, 0.037 mmol) in dichloromethane (0.5mL) was added isonicotinic acid (5.0 mg, 0.040 mmol), HATU (16.7 mg,0.044 mmol) and diisopropylethylamine (0.021 mL, 0.12 mmol). Thereaction mixture was stirred at 25° C. for 2 hrs. and evaporated.Purification of the crude material via reverse phase chromatographyeluting with acetonitrile/water/TFA provided the title compound.

MS (ESI): m/z=835.0 [M+H].

Example 3(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(2-fluorobenzamido)-5,16-dioxo-1,2,3,5,6,7,8,9,01011,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 3 was prepared according to the procedure utilized for thepreparation of Example 2, replacing isonicotinic acid with2-fluorobenzoic acid. Purification of the crude material via reversephase chromatography eluting with acetonitrile/water/TFA provided thetitle compound.

MS (ESI): m/z=851.9 [M+H].

Example 4N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide

Example 4 was prepared according to the procedure utilized for thepreparation of Example 2, replacing isonicotinic acid with5-methylisoxazole-3-carboxylic acid. Purification of the crude materialvia reverse phase chromatography eluting with acetonitrile/water/TFAprovided the title compound.

MS (ESI): m/z=838.9 [M+H].

Example 5(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 5 was prepared according to the procedure utilized for thepreparation of Example 2, replacing isonicotinic acid with5-methylpyrazine-2-carboxylic acid. Purification of the crude materialvia reverse phase chromatography eluting with acetonitrile/water/TFAprovided the title compound.

MS (ESI): m/z=849.9 [M+H].

Example 6N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)isoxazole-5-carboxamide

Example 6 was prepared according to the procedure utilized for thepreparation of Example 2, replacing isonicotinic acid withisoxazole-5-carboxylic acid. Purification of the crude material viareverse phase chromatography eluting with acetonitrile/water/TFAprovided the title compound. MS (ESI): m/z=824.9 [M+H].

Example 7N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)thiazole-4-carboxamide

Example 7 was prepared according to the procedure utilized for thepreparation of Example 2, replacing isonicotinic acid withthiazole-4-carboxylic acid. Purification of the crude material viareverse phase chromatography eluting with acetonitrile/water/TFAprovided the title compound. MS (ESI): m/z=840.9 [M+H].

Example 8(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 8 was prepared according to the procedure utilized for thepreparation of Example 2, replacing isonicotinic acid with1-methyl-1H-pyrazole-3-carboxylic acid. Purification of the crudematerial via reverse phase chromatography eluting withacetonitrile/water/TFA provided the title compound. MS (ESI): m/z=838.0[M+H].

Example 9(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 9 was prepared according to the procedure utilized for thepreparation of Example 2, replacing isonicotinic acid withpyrimidine-4-carboxylic acid. Purification of the crude material viareverse phase chromatography eluting with acetonitrile/water/TFAprovided the title compound. MS (ESI): m/z=835.9[M+H].

Example 10(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1,3-dimethyl-1H-pyrazole-4-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 10 was prepared according to the procedure utilized for thepreparation of Example 2, replacing isonicotinic acid with1,3-dimethyl-1H-pyrazole-4-carboxylic acid. Purification of the crudematerial via reverse phase chromatography eluting withacetonitrile/water/TFA provided the title compound. MS (ESI):m/z=852.0[M+H].

Example 11(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(3-fluorobenzamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 11 was prepared according to the procedure utilized for thepreparation of Example 2, replacing isonicotinic acid with3-fluorobenzoyl chloride. Purification of the crude material via reversephase chromatography eluting with acetonitrile/water/TFA provided thetitle compound. MS (ESI): m/z=838.0 [M+H].

Example 12 tert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamateExample 12a tert-butyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-hydroxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate

To a solution of tert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(9H-fluoren-9-ylideneaminooxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate(20.0 g, 26.8 mmol) in acetic acid (80 ml) stirring at 40° C. was zincdust (10.52 g, 166 mmol). After the addition was complete the reactionmixture was stirred at 40° C. for 1 hour. The mixture was then cooled toroom temperature, diluted with toluene, and filtered through Celite. Themother liquor was washed with water, 1 N HCl, and saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and filtered.The filtrate was then evaporated under reduced pressure to provide thetitle compound 12a (14.8 g, 97% yield).

Example 12b tert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(3-chloroquinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate

A solution of compound 12a (10.0 g, 17.6 mmol), cesium carbonate (17.2,52.8 mmol), and 2,3-dichloroquinoxaline (3.50 g, 17.6 mmol) indimethylformamide (175 ml) was heated to 70° C. for 18 hours. Anadditional portion of 2,3-dichloroquinoxaline (0.70 g, 3.5 mmol) wasadded and the reaction mixture was stirred at 70° C. for 18 hours. Thereaction mixture was cooled to room temperature, and then partitionedbetween ethyl acetate (300 ml) and 1 N HCl (100 ml). The organic layerwas separated, washed with brine (100 ml), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure to obtain thecrude product as a solid. The solid was purified by columnchromatography on silica gel (EtOAc-hexane gradient) to obtain the titlecompound as a solid (4.7 g., 37% yield); MS (ESI): m/z=731.1 [M+H].

Example 12c

To a microwave vessel was added the product from 12b (0.40 g 0.547mmole), benzofuran-2-yltributylstannane (0.245 g., 0.602 mmole),tris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.055 mmol),1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phospha-adamantane (32 mg,0.11 mmol), sodium bicarbonate (46 mg, 0.547 mmol) and dioxane (3 mL).The vessel was evacuated and nitrogen introduced. The mixture wasreacted in a microwave reactor at 110 degrees C. for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 N HCl followed bysaturated aqueous sodium chloride, and dried over anhydrous magnesiumsulfate. The mixture was filtered through Celite and evaporated underreduced pressure. The residue was dissolved in acetonitrile and washedwith hexane (five times) and then evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel (CHCl₃-EtOAcgradient) to obtain the title compound (386 mg., 87% yield). MS (ESI):m/z=813.0 [M+H].

Example 13N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamideExample 13a(2R,6S,13aS,14aR,16aS,Z)-6-amino-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamidehydrochloride

The product of Example 12 (0.386 g, 0.475 mmol) was dissolved in amixture of ethyl acetate (2.4 mL) and 4 N HCl in dioxane (2.4 mL) andstirred at room temperature for one hour. The mixture was thenevaporated under reduced pressure to provide the title compound (0.338mg, 100% yield).

Example 13b

A mixture of the product of Example 13a (30 mg, 0.040 mmol),5-methylisoxazole-3-carboxylic acid (5.1 mg, 0.040 mmol),N-ethyl-N-isopropylpropan-2-amine (15.6 mg, 0.12 mmol), and HATU (18.3mg, 0.048 mmol) in dichloromethane (0.5 mL) was stirred at roomtemperature for one hour and then evaporated. Purification of the crudematerial via reverse phase chromatography eluting withacetonitrile/water/TFA provided the title compound (14 mg, 42% yield).MS (ESI): m/z=822.0[M+H].

Example 14(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 14 was prepared according to the procedure utilized for thepreparation of Example 13, replacing 5-methylisoxazole-3-carboxylic acidwith 5-methylpyrazine-2-carboxylic acid.

Purification of the crude material via reverse phase chromatographyeluting with acetonitrile/water/TFA provided the title compound.

MS (ESI): m/z=833.0 [M+H].

Example 15(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 15 was prepared according to the procedure utilized for thepreparation of Example 13, replacing 5-methylisoxazole-3-carboxylic acidwith 1-methyl-1H-pyrazole-3-carboxylic acid. Purification of the crudematerial via reverse phase chromatography eluting withacetonitrile/water/TFA provided the title compound.

MS (ESI): m/z=821.1 [M+H].

Example 16(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 16 was prepared according to the procedure utilized for thepreparation of Example 13, replacing 5-methylisoxazole-3-carboxylic acidwith 1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Purification of thecrude material via reverse phase chromatography eluting withacetonitrile/water/TFA provided the title compound.

MS (ESI): m/z=835.0 [M+H].

Example 17(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 17 was prepared according to the procedure utilized for thepreparation of Example 13, replacing 5-methylisoxazole-3-carboxylic acidwith pyrimidine-4-carboxylic acid. Purification of the crude materialvia reverse phase chromatography eluting with acetonitrile/water/TFAprovided the title compound.

MS (ESI): m/z=818.9 [M+H].

Example 18 tert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate

Example 18 was prepared according to the procedure utilized for thepreparation of Example 12, replacing benzofuran-2-yltributylstannanewith benzo[b]thiophen-2-yltributylstannane. Purification of the crudematerial via silica gel chromatography eluting with hexane/ethyl acetate(1:2) provided the title compound.

MS (ESI): m/z=829.1 [M+H].

Example 19N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamideExample 19a(2R,6S,13aS,14aR,16aS,Z)-6-amino-2-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamidehydrochloride

The product of Example 18 (0.296 g, 0.357 mmol) was dissolved in amixture of ethyl acetate (1.7 mL) and 4 N HCl in dioxane (1.7 mL) andstirred at room temperature for one hour. The mixture was thenevaporated under reduced pressure to provide the title compound (0.262mg, 96% yield).

Example 19b

A mixture of the product of Example 19a (30 mg, 0.039 mmol),5-methylisoxazole-3-carboxylic acid (5.0 mg, 0.039 mmol),N-ethyl-N-isopropylpropan-2-amine (15.2 mg, 0.118 mmol), and HATU (17.9mg, 0.047 mmol) in dichloromethane (0.5 mL) was stirred at momtemperature for one hour and then evaporated. Purification of the crudematerial via reverse phase chromatography eluting withacetonitrile/water/TFA provided the title compound (18 mg, 53% yield).MS (ESI): m/z=837.9[M+H].

Example 20(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 20 was prepared according to the procedure utilized for thepreparation of Example 19, replacing 5-methylisoxazole-3-carboxylic acidwith 5-methylpyrazine-2-carboxylic acid. Purification of the crudematerial via reverse phase chromatography eluting withacetonitrile/water/TFA provided the title compound.

MS (ESI): m/z=848.7 [M+H].

Example 21(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,1414,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 21 was prepared according to the procedure utilized for thepreparation of Example 19, replacing 5-methylisoxazole-3-carboxylic acidwith 1-methyl-1H-pyrazole-3-carboxylic acid. Purification of the crudematerial via reverse phase chromatography eluting withacetonitrile/water/TFA provided the title compound.

MS (ESI): m/z=836.9 [M+H].

Example 22(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 22 was prepared according to the procedure utilized for thepreparation of Example 19, replacing 5-methylisoxazole-3-carboxylic acidwith 1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Purification of thecrude material via reverse phase chromatography eluting withacetonitrile/water/TFA provided the title compound.

MS (ESI): m/z=851.0 [M+H].

Example 23(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[b]thiophen-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 23 was prepared according to the procedure utilized for thepreparation of Example 19, replacing 5-methylisoxazole-3-carboxylic acidwith pyrimidine-4-carboxylic acid. Purification of the crude materialvia reverse phase chromatography eluting with acetonitrile/water/TFAprovided the title compound.

MS (ESI): m/z=835.1 [M+H].

Example 24 tert-butyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamateExample 24a (2S,6S,13aS,14aR,16aS,Z)-ethyl2-(4-bromophenylsulfonyloxy)-6-(tert-butoxycarbonylamino)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate

A solution of (2S,6S,13aS,14aR,16aS,Z)-ethyl6-(tert-butoxycarbonylamino)-2-hydroxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate(22.1 g, 44.8 mmol) and DABCO (8.5 g, 76.7 mmol) in toluene (88 mL) wasstirred at room temperature. To this solution was added a solution of4-bromobenzene-1-sulfonyl chloride 17.2 g, 67.2 mmol) in toluene (44mL). After the addition was complete the reaction mixture was quenchedwith 10% aqueous sodium carbonate (110 mL) and the mixture stirred for15 min. Tetrahydrofuran (44 mL) was added and the mixture was washedwith 0.5 M HCl, water, and then saturated aqueous sodium chloride. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andevaporated under reduced pressure and dried to provide the titlecompound (27.7 g, 87% yield), which was used without furtherpurification.

Example 24b (2R,6S,13aS,14aR,16aS,Z)-ethyl6-(tert-butoxycarbonylamino)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate

To a solution of the compound of Example 24a (11.0 g, 15.4 mmol) in NMP(100 ml) was added phenanthridine-6(5H)-one (3.15 g. 16.2 mmol) followedby Cs₂CO₃ (7.53 g, 23.1 mmol). The resulting mixture was heated to 55°C. for four hours. The reaction mixture was cooled to room temperature,and then partitioned between ethyl acetate (250 ml) and 5% aqueoussodium bicarbonate solution (200 ml). The organic layer was separated,washed with 5% aqueous sodium bicarbonate solution (200 ml) followed bybrine (150 ml), dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to obtain the crude product as a solid. The solidwas then dissolved in methyl t-butyl ether (200 ml), the resultingsuspension was stirred at room temperature for 1 hour and filtered. Thefiltrate contained the desired product was concentrated under reducedpressure to obtain 7.95 g of product 24b as a solid; MS-DCI/NH₃: 671(M+H)⁺.

Example 24c(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylicacid (24c)

To a solution of the product of Example 246 (7.8 g, 11.6 mmol) intetrahydrofuran (40 ml)/ethanol (40 ml) was added an aqueous lithiumhydroxide solution (0.84 g of lithium hydroxide in 40 ml of H₂O). Theresulting mixture was heated to 50° C. for two hours and cooled to roomtemperature. The organic solvents were mostly removed under reducedpressure, and the resulting residue was acidified with 10% citric acidaqueous solution and extracted with ethyl acetate (200 ml). The organiclayer was separated, washed with brine (200 ml), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give a lightyellow solid, which was further dried in a vacuum oven at 45° C. for 18h to afford 7.5 g of product 24c as a light yellow solid, MS-DCI/NH₃:643 (M+H)⁺.

Example 24d tert-butyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate

To a solution of product of Example 24c (7.46 g, 11.6 mmol) in DMF (80ml) was added 1,1′-carbonyldiimidazole (5.64 g, 34.8 mmol). The reactionmixture was stirred at room temperature for 6 hours. To the abovesolution was then added cyclopropanesulfonamide (4.21 g, 34.8 mmol)followed by DBU (5.73 ml, 36.0 mmol). The resulting mixture was stirredat room temperature for 14 hours. To the reaction mixture was addedEtOAc (200 ml),10% aqueous citric acid solution (200 ml) and saturatedaqueous sodium chloride (50 ml). The organic layer was separated, washedwith saturated aqueous sodium chloride (100 ml), dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (ethylacetate/heptane gradient) to obtain the title compound as a white solid(6.40 g, 74% yield). MS (ESI): m/z=746.1 [M+H].

Example 25(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-6-(pyrazine-2-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamideExample 25a(2R,6S,13aS,14aR,16aS,Z)-6-amino-N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamidehydrochloride

To a suspension of the product of Example 24 (0.35 g, 0.47 mmol) inacetonitrile (5 mL) was added a 4 M solution of HCl in dioxane (0.6 mL,2.4 mmol). The reaction mixture was stirred at room temperature for 4 h.The solvent was evaporated under reduced pressure and the resultingsolid dried under vacuum to provide the title compound (0.32 g, quant.yield).

Example 25b(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-6-(pyrazine-2-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

To a solution of Example 25a (320 mg, 0.47 mmol) in dimethylformamide (5mL) was added pyrazinecarboxylic acid (0.065 g, 0.52 mmol), HATU (214mg, 0.56 mmol) and diisopropylethylamine (0.2 mL, 1.18 mmol). Thereaction mixture was stirred at 25° C. for 2 h and then partitionedbetween 5% aqueous sodium bicarbonate and ethyl acetate. The organiclayer was dried over anhydrous magnesium sulfate, filtered, andevaporated. The residue was purified by crystallization from ethylacetate I hexane to give the desired product (155 mg, 44% yield) as anoff-white solid.

MS (ESI): m/z=752.0 [M+H].

Example 26 Cyclopentyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamateExample 26a (2R,6S,13aS,14aR,16aS,Z)-ethyl6-(cyclopentyloxycarbonylamino)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14.14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate

Example 26a was prepared according to the procedure utilized for thepreparation of Example 24b, replacing the compound of Example 24a withcompound (2S,6S,13aS,14aR,16aS,Z)-ethyl2-(4-bromophenylsulfonyloxy)-6-(cyclopentyloxycarbonylamino)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate,to provide the title compound.

MS (DCI/NH₃): m/z=683.0 [M+H]

Example 26b(2R,6S,13aS,14aR,16aS,Z)-6-(cyclopentyloxycarbonylamino)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylicacid

Example 26b was prepared according to the procedure utilized for thepreparation of Example 24c, replacing compound 24b with compound 26a, toprovide the title compound.

MS (DCI/NH₃): m/z=655.0 [M+H].

Example 26c Cyclopentyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate

The title compound of Example 26 was prepared according to the procedureutilized for the preparation of Example 24, replacing compound 24c withcompound 26b, to provide the title compound.

MS (DCI/NH₃): m/z=758.0 [M+H].

Example 27(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(5-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 27 was prepared according to the procedure utilized for thepreparation of Example 25, replacing 2-pyrazinecarboxylic acid with5-methyl-1H-pyrazole-3-carboxylic acid. Purification of the crudematerial via reverse phase chromatography eluting withacetonitrile/water/TFA provided the title compound.

MS (ESI): m/z=754.2 [M+H].

Example 28N-((2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide

Example 28 was prepared according to the procedure utilized for thepreparation of Example 25, replacing 2-pyrazinecarboxylic acid with5-methylisoxazole-3-carboxylic acid. Purification of the crude materialvia reverse phase chromatography eluting with acetonitrile/water/TFAprovided the title compound.

MS (ESI): m/z=755.1 [M+H].

Example 29(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 29 was prepared according to the procedure utilized for thepreparation of Example 25, replacing 2-pyrazinecarboxylic acid with5-methylpyrazine-2-carboxylic acid. Purification of the crude materialvia reverse phase chromatography eluting with acetonitrile/water/TFAprovided the title compound.

MS (ESI): m/z=766.1 [M+H].

Example 30N-((2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)thiazole-5-carboxamide

Example 30 was prepared according to the procedure utilized for thepreparation of Example 25, replacing 2-pyrazinecarboxylic acid withthiazole-5-carboxylic acid. Purification of the crude material viareverse phase chromatography eluting with acetonitrile/water/TFAprovided the title compound.

MS (ESI): m/z=757.1 [M+H].

Example 31(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(2-fluorobenzamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 31 was prepared according to the procedure utilized for thepreparation of Example 25, replacing 2-pyrazinecarboxylic acid with2-fluorobenzoic acid. Purification of the crude material via reversephase chromatography eluting with acetonitrile/water/TFA provided thetitle compound.

MS (ESI): m/z=768.1 [M+H].

Example 32(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-6-(pyridazine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 32 was prepared according to the procedure utilized for thepreparation of Example 25, replacing 2-pyrazinecarboxylic acid withpyridazine-4-carboxylic acid. Purification of the crude material viareverse phase chromatography eluting with acetonitrile/water/TFAprovided the title compound.

MS (ESI): m/z=752.1 [M+H].

Example 33(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,1,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 33 was prepared according to the procedure utilized for thepreparation of Example 25, replacing 2-pyrazinecarboxylic acid withpyrimidine-4-carboxylic acid. Purification of the crude material viareverse phase chromatography eluting with acetonitrile/water/TFAprovided the title compound.

MS (ESI): m/z=752.1 [M+H].

Example 34(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(1-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 34 was prepared according to the procedure utilized for thepreparation of Example 25, replacing 2-pyrazinecarboxylic acid with1-methyl-1H-pyrazole-3-carboxylic acid. Purification of the crudematerial via reverse phase chromatography eluting withacetonitrile/water/TFA provided the title compound.

MS (ESI): m/z=754.2 [M+H].

Example 35(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(2-hydroxy-2-methylpropanamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,156,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][,4]diazacyclopentadecine-14a-carboxamide

Example 35 was prepared according to the procedure utilized for thepreparation of Example 25, replacing 2-pyrazinecarboxylic acid with2-hydroxy-2-methylpropanoic acid. Purification of the crude material viareverse phase chromatography eluting with acetonitrile/water/TFAprovided the title compound.

MS (ESI): m/z=732.2 [M+H].

Example 36(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,1,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 36 was prepared according to the procedure utilized for thepreparation of Example 25, replacing 2-pyrazinecarboxylic acid with1,5-dimethyl-1H-pyrazole-3-carboxylic acid. Purification of the crudematerial via reverse phase chromatography eluting withacetonitrile/water/TFA provided the title compound.

MS (ESI): m/z=768.1 [M+H].

Example 37 Cyclopentyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(2-fluorophenanthridin-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamateExample 37a 5′-Fluoro-2′-nitrobiphenyl-2-carboxylate

To a microwave vessel was added 2-(methoxycarbonyl)phenylboronic acid(63.4 mg, 0.352 mmol), 2-bromo-4-fluoro-1-nitrobenzene (77 mg, 0.35mmol), diacetoxypalladium (0.93 mg, 4.1 μmol) anddicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (3.47 mg, 8.45μmol). Ethanol (1760 μl) and sodium carbonate (176 μl, 0.352 mmol) wereadded and the mixture was reacted in a microwave reactor at 100° C. for30 min. The reaction mixture was diluted with dichloromethane, driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by preparative thin layerchromatography (eluant: 9:1 hexane/ethyl acetate) to provide methyl5′-fluoro-2′-nitrobiphenyl-2-carboxylate (37a, 54.8 mg, 0.199 mmol,56.6% yield).

Example 37b 2-fluoro-5-hydroxyphenanthridin-6(5H)-one

To a solution of the product of Example 37a (methyl5′-fluoro-2′-nitrobiphenyl-2-carboxylate, 56.79 mg, 0.206 mmol) inmethanol (9 mL) was added 10% palladium on carbon (15.6 mg, 0.015 mmol).The flask was fitted with a hydrogen balloon and de-gassed three timeswith hydrogen. The reaction mixture was stirred, diluted withdimethylformamide, and filtered. The filtrate was concentrated toprovide 2-fluoro-5-hydroxyphenanthridin-6(5H)-one (37b, 46.36 mg, 0.202mmol, 98% yield).

Example 37c 2-Fluorophenanthridin-6(5H)-one

A mixture of the product of Example 37b(2-fluoro-5-hydroxyphenanthridin-6(5H)-one, 46.4 mg, 0.202 mmol), aceticacid (3 mL), and zinc (99 mg, 1.517 mmol) was heated under reflux at130° C. for 1 h. The mixture was diluted with dimethylformamide andfiltered and the filtrate was concentrated to give a tan solid (100 mg).The solid was partitioned between dichloromethane/dimethylformamide(2/1, 50 mL) and sodium carbonate (10 ml). The organic layer was washedwith water (2×10 ml) and concentrated to provide2-fluorophenanthridin-6(5H)-one (37c, 38.2 mg, 88% yield).

Example 37d (2R,6S,13aS,14aR,16aS,Z)-ethyl6-(cyclopentyloxycarbonylamino)-2-(2-fluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate

Example 37d was prepared according to the procedure used for thepreparation of Example 37b, substituting (2S,6S,13aS,14aR,16aS,Z)-ethyl2-(4-bromophenylsulfonyloxy)-6-(cyclopentyloxycarbonylamino)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylatefor 1a, and substituting 2-fluorophenanthridin-6(5H)-one (80c) forphenanthridin-6(5H)-one, to provide the title compound in 48% yield.

Example 37e(2R,6S,13aS,14aR,16aS,Z)-6-(cyclopentyloxycarbonylamino)-2-(2-fluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylicacid

Example 37e was prepared according to the procedure used for thepreparation of Example 67c, substituting the product of Example 37d forthe product of Example 24b.

Example 37f Cyclopentyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(2-fluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate

The compound of Example 37 was prepared according to the procedure usedfor the preparation of Example 24, substituting the product of Example37e for the product of Example 24c (14.6 mg, 78% yield).

MS (ESI): m/z=776.1 [M+H].

Example 38 tert-Butyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(2,9-difluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamateExample 38a Methyl 5,5′-difluoro-2′-nitrobiphenyl-2-carboxylate

To 2-bromo-4-fluoro-1-nitrobenzene (185.16 mg, 0.842 mmol) was addedPd₂dba₃ (23.12 mg, 0.025 mmol) and copper powder (271 mg, 4.26 mmol).Dimethylsulfoxide (2.3 ml) and methyl 2-bromo-4-fluorobenzoate (0.122ml, 0.842 mmol) were added and the mixture was stirred vigorously at100° C. for 2 h. The mixture was cooled to room temperature, dilutedwith ethyl acetate (20 ml), and filtered. The filtrate was washed withwater and dried (anhydrous Na₂SO₄) and concentrated to give a yellow oil(279.8 mg). This oil was utilized without purification for thepreparation of Example 38b.

Example 38b 2,9-Difluoro-5-hydroxyphenanthridin-6(5H)-one

To the product of Example 38a (279.8 mg) was added methanol (7.5 mL) and10% palladium on carbon (76 mg, 0.071 mmol). The flask was fitted with ahydrogen balloon and the mixture was de-gased and back-filled withhydrogen three times. The mixture was stirred under hydrogen for 16 h,diluted with dimethylformamide and filtered. The filtrate wasconcentrated to give a red solid. This material was triturated withdichloromethane/hexane (9/1) and filtered to provide the title compound(Example 38b, 43.15 mg, 0.175 mmol, quantitative yield).

Example 38c 2,9-Difluorophenanthridin-6(5H)-one

Example 38c was prepared according to the procedure used for thepreparation of Example 37c, substituting the product of Example 38b forthe product of Example 80b.

Example 38d (2R,6S,13aS,14aR,16aS,Z)-ethyl6-(tert-butoxycarbonylamino)-2-(2,9-difluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate

Example 38d was prepared according to the procedure used for thepreparation of Example 24c, substituting the product of Example 38c forphenanthridine-6(5H)-one.

Example 38e(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-2-(2,9-difluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylicacid

Example 38e was prepared according to the procedure used for thepreparation of Example 24c, substituting the product of Example 38d forthe product of Example 24b.

Example 38f tert-Butyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(2,9-difluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate

Example 38 was prepared according to the procedure used for thepreparation of Example 24, substituting the product of Example 38e forthe product of Example 24c.

MS (ESI): m/z=782.1 [M+H].

Example 39 tert-butyl(2R,6S,13aR,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate

Argon degassed ethanol (0.8 ml) was added to the product of Example 24(79.1 mg, 0.106 mmol) and Crabtree's Catalyst (3.45 mg, 4.24 μmol) (4mole %) in a 4 mL pressure bottle. The vessel was sparged three timeswith argon and then pressurized with hydrogen (50 psi). The mixture washeated to 50° C. under hydrogen and stirred for 4.5 hr at 50° C.

The reaction mixture was concentrated and purified by reverse phasechromatography, eluting with an acetonitrile (1% TFA)/water gradient toprovide the title compound as a white solid (70.41 mg, 0.094 mmol, 89%yield).

MS (ESI): m/z=748.2 [M+H].

Example 40 Cyclopentyl(2R,6S,13aR,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate

Example 40 was prepared according to the procedure utilized for thepreparation of Example 39, replacing the product of Example 24 with theproduct of Example 26.

MS (ESI): m/z=760.2 [M+H].

Example 41 tert-Butyl(2R,6S,13aR,14aR,16aS)-5,16-dioxo-2-(phenanthridin-6-yloxy)-14a-(thiophen-2-ylsulfonylcarbamoyl)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate

Example 41 was prepared according to the procedure utilized for thepreparation of Example 24, replacing cyclopropanesulfonamide withthiophene-2-sulfonamide.

MS (ESI): m/z=788.0 [M+H].

Example 42(2R,6,3S,3S,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(2-methyl)pyrimidine-5-carboxamido)-5,16-dioxo-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamideExample 42a (S)-2-(2-methylpyrimidine-5-carboxamido)non-8-enoic acid

Boc-2(S)-amino-non-8-eoic acid dicyclohexylamine salt can be suspendedin isopropyl acetate, washed several times with an aqueous citric acidsolution and then once with water. The washed product, concentrated andthen re-diluted in isopropyl acetate, can be reacted with HCl to produce2(S)-amino-non-8-eoic acid HCl salt. 2-Methylpyrimidine-5-carboxylicacid, N,N′-disuccinimidyl carbonate, and N,N-dimethylaminopyridine canbe dissolved in N-methyl-2-pyrrolidone (NMP) and stirred.2(S)-Amino-non-8-eoic acid HCl salt is subsequently added, followed bytriethylamine, and stirred to produce the title compound of Example 42a,which can be crystallized out by adding HCl followed by water.

Example 42b(1R,2S)-ethyl-1-((2S,4R)—N-(tert-butoxycarbonyl)-1-((S)-2-(2-methylpyrimidine-5-carboxamido)non-8-enoyl)-4-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate

(2S,4R)—N-Boc-4-hydroxyproline can be reacted with2-chloro-3-(thiophen-2-yl)quinoxaline in NMP, in the presence of sodiumt-butoxide, to produce(2S,4R)-1-(tert-butoxycarbonyl)-4-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)pyrrolidine-2-carboxylicacid. Methyl tertiary butyl ether (MTBE) and water can then be added.The aqueous layer is separated, washed, and then HCl is added, followedby extraction with MTBE. The extracted product can be mixed withdiisopropylethylamine (DIPEA) and HATU (CAS #148893-10-1), and thenreacted with (1R,2S)-ethyl-1-amino-2-vinylcyclopropanecarboxylatetosylate salt in dimethylformide (DMF) and toluene. The reactionproduces (2S,4R)-tert-butyl2-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)pyrrolidine-1-carboxylate,which can be extracted with MTBE and washed with HCl, further extracted,washed, dried, and dissolved in 2-propanol.

HCl can be added to the 2-propanol solution to produce (1R,2S)-ethyl1-((2S,4R)-4-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate,which can be crystallized out by neutralizing with NaOH.

(1R,2S)-ethyl1-((2S,4R)-4-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate,the title compound of Example 42a,N-hydroxy-5-norbornene-2,3-dicarboximide, andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride can bemixed and stirred in DMF for hours, followed by addition ofN,N-dimethylethylene diamine. The reaction produces (1R,2S)-ethyl1-((2S,4R)-1-((S)-2-(2-methylpyrimidine-5-carboxamido)non-8-enoyl)-4-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate,which can be dissolved in isopropyl acetate and extracted with aqueousH₃PO₄, and then extracted with aqueous K₂HPO₄.

The product can be reacted with di-tert-butyldicarbonate in the presenceof dimethylaminopyridine, followed by extraction with a mixture of acitric acid solution and a sodium chloride solution, to produce thetitle compound of Example 42b.

Example 42c(2R,6S,13aS,14aR,16aS,Z)-ethyl-6-(2-methylpyrimidine-5-carboxamido)-5,16-dioxo-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylatehydrochloride

The product of Example 42b can be subject to ring-closing metathesis inthe presence of Zhan-B catalyst in toluene to produce(2R,6S,13aS,14aR,16aS,Z)-15-tert-butyl 14a-ethyl6-(2-methylpyrimidine-5-carboxamido)-5,16-dioxo-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-2,3,5,6,7,8,9,10,11,13a,14,14a,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a,15(1H)-dicarboxylate. The catalyst can be quenched with imidazole afterthe reaction.

The ring-closed product in toluene can be solvent switched toacetonitrile, followed by addition of hydrogen chloride in dioxane andheated to produce the title compound of Example 42c.

Example 42d(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(2-methylpyrimidine-5-carboxamido)-5,16-dioxo-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

The isolated product of Example 42c can be mixed with tetrahydrofuran,water and LiOH.H₂O, and then heated and stirred. The reaction mixturecan be later cooled, added with aqueous H₃PO₄, aqueous NaCl and 2-methyltetrahydrofuran, and the organic layer is separated, washed andfiltered. MeCN is added to the concentrated organic layer, heated andcooled, and then diethylamine is added. The slurry is heated and cooledto form(2R,6S,13aS,14aR,16aS,Z)-6-(2-methylpyrimidine-5-carboxamido)-5,16-dioxo-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylatediethylamine salt, which can be further washed and dried.

The diethylamine salt can be mixed with tetrahydrofuran, 2-methyltetrahydrofuran and aqueous H3PO4. The organic layer is separated,washed with aqueous NaCl, and then concentrated and/or purified. Theproduct can be subsequently mixed with NMP, followed by addition ofcarbonyldiimidazole (CDI) and then 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU). Cyclopropylsulfonamide can be subsequently added. The reactionmixture is stirred for hours. Isopropyl acetate can then be added,followed by aqueous KH₂PO₄ and then aqueous H₃PO₄. The organic layer canbe isolated, washed, and purified to produce the title compound ofExample 42d.

Example 43N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-3-methylisoxazole-5-carboxamide

Example 43 can be prepared according to the procedure described for thepreparation of Example 42, replacing 2-methylpyrimidine-5-carboxylicacid from Example 42a with 3-methylisoxazole-5-carboxylic acid inExample 43a to produce(S)-2-(3-methylisoxazole-5-carboxamido)non-8-enoic acid. All subsequentsteps should proceed in a similar fashion to Example 42 to produceExample 43.

Example 44N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methyisoxazole-3-carboxamide

Example 44 can be prepared according to the procedure described for thepreparation of Example 42, replacing 2-methylpyrimidine-5-carboxylicacid from Example 42a with 5-methylisoxazole-3-carboxylic acid inExample 44a to produce(S)-2-(5-methylisoxazole-3-carboxamido)non-8-enoic acid. All subsequentsteps should proceed in a similar fashion to Example 42 to produceExample 44.

Example 45(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(3-fluorobenzamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 45 can be prepared according to the procedure described for thepreparation of Example 42, replacing 2-methylpyrimidine-5-carboxylicacid from Example 42a with 3-fluorobenzoic acid in Example 45a toproduce (S)-2-(3-fluorobenzamido)non-8-enoic acid. All subsequent stepsshould proceed in a similar fashion to Example 42 to produce Example 45.

Example 46(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 46 can be prepared according to the procedure described for thepreparation of Example 42, replacing 2-methylpyrimidine-5-carboxylicacid from Example 42a with pyrimidine-4-carboxylic acid in Example 46ato produce (S)-2-(pyrimidine-4-carboxamido)non-8-enoic acid. Allsubsequent steps should proceed in a similar fashion to Example 42 toproduce Example 46.

Example 47N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)isoxazole-5-carboxamide

Example 47 can be prepared according to the procedure described for thepreparation of Example 42, replacing 2-methylpyrimidine-5-carboxylicacid from Example 42a with isoxazole-5-carboxylic acid in Example 47a toproduce (S)-2-(isoxazole-5-carboxamido)non-8-enoic acid.

All subsequent steps should proceed in a similar fashion to Example 42to produce Example 47.

Example 48(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 48 can be prepared according to the procedure described for thepreparation of Example 42, replacing 2-methylpyrimidine-5-carboxylicacid from Example 42a with 5-methylpyrazine-2-carboxylic acid in Example48a to produce (S)-2-(5-methylpyrazine-2-carboxamido)non-8-enoic acid.All subsequent steps should proceed in a similar fashion to Example 42to produce Example 48.

Example 49(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamideExample 49a (S)-2-(5-methylpyrazine-2-carboxamido)non-8-enoic acid

Boc-2(S)-amino-non-8-eoic acid dicyclohexylamine salt can be suspendedin isopropyl acetate, washed several times with an aqueous citric acidsolution and then once with water. The washed product, concentrated andthen re-diluted in isopropyl acetate, can be reacted with HCl to produce2(S)-amino-non-8-eoic acid HCl salt. 5-Methyl-2-pyrazinecarboxylic acid,N,N′-disuccinimidyl carbonate, and N,N-dimethylaminopyridine can bedissolved in N-methyl-2-pyrrolidone (NMP) and stirred.2(S)-Amino-non-8-eoic acid HCl salt is subsequently added, followed bytriethylamine, and stirred to produce the title compound of Example 49a,which can be crystallized out by adding HCl followed by water.

Example 49b(1R,2S)-ethyl-1-((2S,4R)—N-(tert-butoxycarbonyl)-1-((S)-2-(5-methylpyrazine-2-carboxamido)non-8-enoyl)-4-(phenanthridin-6-yloxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate

(2S,4R)—N-Boc-4-hydroxyproline can be reacted with6-chlorophenanthridine in NMP, in the presence of sodium t-butoxide, toproduce(2S,4R)-1-(tert-butoxycarbonyl)-4-(phenanthridin-6-yloxy)pyrrolidine-2-carboxylicacid. Methyl tertiary butyl ether (MTBE) and water can then be added.The aqueous layer is separated, washed, and then HCl is added, followedby extraction with MTBE. The extracted product can be mixed withdiisopropylethylamine (DIPEA) and HATU (CAS #148893-10-1), and thenreacted with (1R,2S)-ethyl-1-amino-2-vinylcyclopropanecarboxylatetosylate salt in dimethylformide (DMF) and toluene. The reactionproduces (2S,4R)-tert-butyl2-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(phenanthridin-6-yloxy)pyrrolidine-1-carboxylate,which can be extracted with MTBE and washed with HCl, further extracted,washed, dried, and dissolved in 2-propanol.

HCl can be added to the 2-propanol solution to produce (1R,2S)-ethyl1-((2S,4R)-4-(phenanthridin-6-yloxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate,which can be crystallized out by neutralizing with NaOH.

(1R,2S)-ethyl1-((2S,4R)-4-(phenanthridin-6-yloxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate,the title compound of Example 49a,N-hydroxy-5-norbornene-2,3-dicarboximide, andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride can bemixed and stirred in DMF, followed by addition of N,N-dimethylethylenediamine. The reaction produces (1R,2S)-ethyl1-((2S,4R)-1-((S)-2-(5-methylpyrazine-2-carboxamido)non-8-enoyl)-4-(phenanthridin-6-yloxy)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate,which can be dissolved in isopropyl acetate and extracted with aqueousH₃PO₄, and then extracted with aqueous K₂HPO₄. The product can bereacted with di-tert-butyldicarbonate in the presence ofdimethylaminopyridine, followed by extraction with a mixture of a citricacid solution and a sodium chloride solution, to produce the titlecompound of Example 49b.

Example 49c(2R,6S,13aS,14aR,16aS,Z)-ethyl-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylatehydrochloride

The product of Example 49b can be subject to ring-closing metathesis inthe presence of Zhan-B catalyst in toluene to produce(2R,6S,13aS,14aR,16aS,Z)-15-tert-butyl 14a-ethyl6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-2,3,5,6,7,8,9,10,11,13a,14,14a,16,16a-tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a,15(1H)-dicarboxylate.The catalyst can be quenched with imidazole after the reaction.

The ring-closed product in toluene can be solvent switched toacetonitrile, followed by addition of hydrogen chloride in dioxane andheated to produce the title compound of Example 49c.

Example 49d(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

The isolated product of Example 49c can be mixed with tetrahydrofuran,water and LiOH.H₂O, and then heated and stirred. The reaction mixturecan be later cooled, added with aqueous H₂PO₄, aqueous NaCl and 2-methyltetrahydrofuran, and the organic layer is separated, washed andfiltered. MeCN is added to the concentrated organic layer, heated andcooled, and then diethylamine is added. The slurry is heated and cooledto form(2R,6S,13aS,14aR,16aS,Z)-6-(5-Methylpyrazine-2-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylatediethylamine salt, which can be further washed and dried.

The diethylamine salt can be mixed with tetrahydrofuran, 2-methyltetrahydrofuran and aqueous H3PO4. The organic layer is separated,washed with aqueous NaCl, and then concentrated and/or purified. Theproduct can be subsequently mixed with NMP, followed by addition ofcarbonyldiimidazole (CDI) and then 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU). Cyclopropylsulfonamide can be subsequently added. The reactionmixture is stirred for hours. Isopropyl acetate can then be added,followed by aqueous KH₂PO₄ and then aqueous H₃PO₄. The organic layer canbe isolated, washed, and purified to produce the title compound ofExample 49d. The isolated product can be further dissolved in isopropylacetate and then the solution is diluted with ethanol. Water can beadded to the resulting solution in portion-wise manner with adequatehold-times after each addition to ensure de-super-saturation. Wateraddition is terminated just as the ternary solvent system becomesbi-phasic due to the partial immiscibility of isopropyl acetate,ethanol, water solvent system. The slurry can be stirred for hours andthen the solid is isolated via filtration and drying to produce thecrystalline hydrate of the title compound.

Example 50(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 50 can be prepared according to the procedure described for thepreparation of Example 49, replacing 5-methylpyrazine-2-carboxylic acidfrom Example 49a with -(1,5-dimethyl-1H-pyrazole-3-carboxylic acid inExample 50a to produce(S)-2-(1,5-dimethyl-1H-pyrazole-3-carboxamido)non-8-enoic acid. Allsubsequent steps should proceed in a similar fashion to Example 49 toproduce Example 50.

Example 51(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(5-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 51 can be prepared according to the procedure described for thepreparation of Example 49, replacing 5-methylpyrazine-2-carboxylic acidfrom Example 49a with 5-methyl-1H-pyrazole-3-carboxylic acid in Example51a to produce (S)-2-(5-methyl-1H-pyrazole-3-carboxamido)non-8-enoicacid. All subsequent steps should proceed in a similar fashion toExample 49 to produce Example 51.

Example 52(2R,6S,13aS,4aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(2-fluorobenzamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 52 can be prepared according to the procedure described for thepreparation of Example 49, replacing 5-methylpyrazine-2-carboxylic acidfrom Example 49a with 2-fluorobenzoic acid in Example 52a to produce(S)-2-(2-fluorobenzamido)non-8-enoic acid. All subsequent steps shouldproceed in a similar fashion to Example 49 to produce Example 52.

Example 53(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-6-(pyrazine-2-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide

Example 53 can be prepared according to the procedure described for thepreparation of Example 49, replacing 5-methylpyrazine-2-carboxylic acidfrom Example 49a with pyrazine carboxylic acid in Example 53a to produce(S)-2-(pyrazine-2-carboxamido)non-8-enoic acid. All subsequent stepsshould proceed in a similar fashion to Example 49 to produce Example 53.

Example 54 tert-butyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(thiazolo[4,5-c]quinolin-4-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate

A mixture of 5-bromothiazole-4-carboxylic acid methyl ester (0.521 g,2.35 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(0.514 g. 2.35 mmol), 1,1′-bis(di-t-butylphosphino)ferrocene palladiumchloride (0.060 g, 0.094 mmol), and sodium carbonate (1.17 mL of 2Maqueous solution) in tetrahydrofuran (12 mL) was stirred under nitrogenat rt for 48 h. The reaction mixture was then heated at 50° C. for anadditional 16 h. The reaction mixture was then cooled to rt, dilutedwith dichloromethane (120 mL) and dimethylformamide (40 mL) and washedwith water (20 mL). The resulting solid was isolated by vacuumfiltration to provide the title compound (0.251 mg, 53% yield,thiazolo[4,5-c]quinolin-4(5H)-one).

Example 55 Synthesis of the cyclic peptide precursor

To a solution of Boc-L-2-amino-8-nonenoic acid 42a (1.36 g, 5 mol) andthe commercially available cis-L-hydroxyproline methyl ester 42b (1.09g, 6 mmol) in 15 ml DMF, was added DIEA (4 ml, 4 eq.) and HATU (4 g, 2eq). The coupling was carried out at 0° C. over a period of 1 hour. Thereaction mixture was diluted with 100 mL EtOAc, and followed by washingwith 5% citric acid 2×20 ml, water 2×20 ml, 1M NaHCO₃ 4×20 ml and brine2×10 ml, respectively. The organic phase was dried over anhydrous Na₂SO₄and then was evaporated, affording the dipeptide 42c (1.91 g, 95.8%)that was identified by HPLC (Retention time=8.9 min, 30-70%, 90% B), andMS (found 421.37, M+Na⁺).

The dipeptide 42c (1.91 g) was dissolved in 15 mL of dioxane and 15 mLof 1 N LiOH aqueous solution and the hydrolysis reaction was carried outat room temperature for 4 hours. The reaction mixture was acidified by5% citric acid and extracted with 100 mL EtOAc, and followed by washingwith water 2×20 ml, and brine 2×20 ml, respectively. The organic phasewas dried over anhydrous Na₂SO₄ and then removed in vacuum, yielding thefree carboxylic acid compound 42d (1.79 g, 97%), which was used for nextstep synthesis without need for further purification.

To a solution of the free acid obtained above (1.77, 4.64 mmol) in 5 mlDMF, D-β-vinyl cyclopropane amino acid ethyl ester (0.95 g, 5 mmol),DIEA (4 ml, 4 eq.) and HATU (4 g, 2 eq) were added. The coupling wascarried out at 0° C. over a period of 5 hours. The reaction mixture wasdiluted with 80 mL EtOAc, and followed by washing with 5% citric acid2×20 ml, water 2×20 ml. 1M NaHCO₃ 4×20 ml and brine 2×10 ml,respectively. The organic phase was dried over anhydrous Na₂SO₄ and thenevaporated. The residue was purified by silica gel flash chromatographyusing different ratios of hexanes:EtOAc as elution phase(5:1→3:1→1:1→1:2→1:5). The linear tripeptide 42e was isolated as an oilafter removal of the elution solvents (1.59 g, 65.4%), identified byHPLC (Retention time=11.43 min) and MS (found 544.84, M+Na⁺).

A solution of the linear tripeptide 42e (1.51 g, 2.89 mmol) in 200 mldry DCM was deoxygenated by bubbling N₂. Hoveyda's 1^(st) generationcatalyst (5 mol % eq.) was then added as solid. The reaction wasrefluxed under N₂ atmosphere 12 hours. The solvent was evaporated andthe residue was purified by silica gel flash chromatography usingdifferent ratios of hexanes:EtOAc as elution phase(9:1→5:1→3:1→1:1→1:2→1:5). The cyclic peptide precursor was isolated asa white powder after removal of the elution solvents (1.24 g, 87%),identified by HPLC (Retention time=7.84 min, 30-70%, 90% B), and MS(found 516.28, M+Na⁺).

(2S,6S,13aS,14aR,16aS,Z)-ethyl2-(4-bromophenylsulfonyloxy)-6-(tert-butoxycarbonylamino)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate

A solution of (2S,6S,13aS,14aR,16aS,Z)-ethyl6-(tert-butoxycarbonylamino)-2-hydroxy-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate(22.1 g, 44.8 mmol) and DABCO (8.5 g, 76.7 mmol) in toluene (88 mL) wasstirred at room temperature. To this solution was added a solution of4-bromobenzene-1-sulfonyl chloride 17.2 g, 67.2 mmol) in toluene (44mL). After the addition was complete the reaction mixture was quenchedwith 10% aqueous sodium carbonate (110 mL) and the mixture stirred for15 min. Tetrahydrofuran (44 mL) was added and the mixture was washedwith 0.5 M HCl, water, and then saturated aqueous sodium chloride. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andevaporated under reduced pressure and dried to provide the titlecompound (27.7 g, 87% yield), which was used without furtherpurification.

Example 56 Measurement of Potency of Inhibition with Purified NS3Protease Enzyme

The activity of recombinant HCV NS3 proteases derived from isolatesrepresenting genotypes 1, 2, 3 or 4 is measured by cleavage of thefollowing peptide substrate:

The substrate is labeled with a fluor and a fluorescence quencher.Cleavage results in release of the quencher and an increase influorescence. NS3 protease is incubated with a dilution series ofinhibitor in 150 mM NaCl, 10% Glycerol, 5 mM DTT, with or without 0.01%dodecyl maltoside for either 30 minutes or 300 minutes. Substrate isadded at a concentration of 5 uM to initiate the reaction, andfluorescence is measured at 2 minute intervals for 30 minutes. Enzymeconcentrations range from 10 to 100 nM in the absence of detergent, or10-fold lower in the presence of detergent. Substrate peptides arelabeled with either EDANS and DABCYL (excitation 355 nm, emission 485nm) or TAMRA and QSY (excitation 544 nm, emission 590 nm). For routineIC50 determination, 3-fold serial dilutions starting with initialconcentrations of 100 μM, 200 μM, or 2 mM are used. For compounds withK_(i) values approaching or lower than the enzyme concentration, atight-binding calculation format is used, with 24 dilutions of inhibitorcovering a range of 0 to 100 nM inhibitor. K_(i) values are calculatedusing the tight binding assay format, according to the followingequation:V=A{[(K+I−E)²+4KE])^(1/2)−(K+I−E)}, where I=total inhibitorconcentration, E=active enzyme concentration, K=apparent K _(i) valueand A=[k _(cat))S/2][K _(m)=(S)].Replicon Cell Lines

Two subgenomic replicon cell lines can be used for compoundcharacterization in cell culture: one derived from genotype 1a and onederived from genotype 1b. Both replicon constructs are bicistronicsubgenomic replicons essentially similar to those described byBartenschlager and coworkers (Lohmann et al., Science (1999)285(5424):110-113). The genotype 1a replicon construct contains theNS3-NS5B coding region derived from the H77 strain of HCV (1a-H77)(Blight et al., J Virol (2003) 77(5):3181-3190). The first cistron ofthe construct consists of the first 36 nucleotides of the HCV 1a-H77core gene fused to a firefly luciferase reporter and a neomycinphosphotransferase (Neo) selectable marker. The luciferase and Neocoding regions are separated by the FMDV 2a protease. The second cistroncontains the NS3-NS5B coding region derived from 1a-H77 with theaddition of adaptive mutations E1202G in NS3, KL691R in NS4A, and K2040Rand S2204I in NS5A. The 1b-Con-1 replicon construct is identical to the1a-H77 replicon, except that the 5′ and 3′ NTRs and the NS3-NS5B codingregion can be derived from the 1b-Con-1 strain (Blight et al., Science(2000) 290(5498):1972-1974), and the adaptive mutations are E1202G andT1280I in NS3 and S2204I in NS5A.

Replicon Compound Testing

Replicon cell lines can be maintained in Dulbecco's modified Eaglesmedium (DMEM) containing 100 IU/ml penicillin, 100 mg/ml streptomycin(Invitrogen), 200 mg/ml G418 (Invitrogen) and 10% (v/v) fetal bovineserum (FBS). Replicon-containing cells can be seeded into 96 well platesat a density of 5000 cells per well in 100 μl DMEM containing 5% FBS.The next day, the compound can be initially diluted in dimethylsulfoxide (DMSO) to generate a 200× stock of the inhibitor in a seriesof 8 half-log dilutions. The dilution series can then be diluted100-fold in the medium containing 5% FBS. One hundred microliters ofmedium with the inhibitor can be added to each well of the overnightcell culture plate already containing 100 μl of DMEM with 5% FBS. Inassays where the protein binding effect on inhibitor potency isassessed, the medium from the overnight cell culture plates can bereplaced with 200 dl DMEM containing 40% human plasma (InnovativeResearch) plus 5% FBS as well as compound. The cells can be grown for 4days in tissue culture incubators. The inhibitory effects of compoundsagainst the replicons can be determined by measuring either the level ofluciferase or HCV RNA. The luciferase assay can be conducted using aLuciferase Assay System kit (Promega) following the manufacturer'sinstructions. Briefly, the cell culture medium is removed and wells arewashed with 200 μl of phosphate-buffered saline. To each well PassiveLysis buffer (Promega, Wis.) is added and the plates are incubated for30 min with rocking to lyse the cells. Luciferin solution (50 μl,Promega) is added, and luciferase activity is measured with a Victor IIluminometer (Perkin-Elmer). To determine HCV RNA levels, RNA extractionscan be performed using the CellsDirect kit (Invitrogen), and the HCV RNAcopy number can be measured using the SuperScript II Platinum One-StepqRT-PCR system (Invitrogen) and primers specific to the HCV 5′nontranslated region. Cytotoxicity can be determined by the3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT)colorimetric assay as follows. Replicon cells is plated in 96-wellplates (4000 cells per well), the next day compound dilutions are addedas in the activity assay, and the cells are grown in the presence of theinhibitors for 4 days. The MTT solution is diluted in DMEM containing 5%FBS and 60 μl of the solution is added to the cells. After 4 hrs, thecells are solubilized by the addition of 30 μl SDS (20% in 0.02 N HCl).The plates are incubated overnight and the optical density can bemeasured at 570 nm.

To determine compounds' EC₅₀ and TD₅₀, luciferase, RNA inhibition andMIT data can be analyzed using the GraphPad Prism 4 software (equation:sigmoidal dose-response—variable slope).

Mutants in Transient Replicons

Mutations detected in resistance selection studies can be introducedinto wild type transient replicon constructs based on genotypes 1a-H77and 1b-N. Both replicons are bicistronic sub-genomic constructscontaining a firefly luciferase reporter similar to those describedabove, but they do not contain a Neo selectable marker and are thereforeonly suitable for transient replication assays. The 1a-H77 replicon fortransient assays further differs from the replicon in the stable cellline in that it contains NS2 through NS5B in the second cistron. The1b-N strain replicon contains NS3 through NS5B in the second cistron,with adaptive mutations E1202G in NS3 and S2204I in NS5A. Mutagenesiscan be performed using the Stratagene QuikChange XL II site-directedmutagenesis kit. Mutants' sequences can be confirmed, plasmids can belinearized with Xba I restriction enzyme and used as template for invitro transcription reactions to make mutant replicon RNA for transienttransfections. In vitro transcription can be performed with the T7Megascript kit (Ambion).

Transient replicon transfections can be performed essentially asdescribed by Mo et al. (Antimicrob Agents Chemother (2005)49(10):4305-4314) with slight modifications. Fifteen micrograms oftemplate RNA can be used to electroporate 3×10⁶ cells in a 200 μl volumein a 0.2 cm cuvette. The cells used for transient transfections can beHuh7 cells obtained by curing replicon-containing cells with IFN (Mo etal., supra). Electroporation can be done with a Gene Pulser II (Bio-Rad,CA) at 480V and 25 μF, using two manual pulses. Transfected cells can bediluted to 7.5×10⁴ cells/ml and plated in % well plates at 7.5×10³ cellsper well in DMEM with 5% FBS and 100 IU/ml penicillin, 100 mg/mlstreptomycin (Invitrogen). Four hours post-transfection, one plate isharvested for luciferase measurement; this plate may provide a measureof the amount of input RNA that can be translated, and thus oftransfection efficiency. To the remaining plates, test compound serialdilutions in DMSO can be added (0.5% DMSO final concentration), andplates are incubated for 4 days.

Exemplary compounds of the present invention were tested for theiranti-HCV activities. Many of the compounds tested showed unexpectedanti-HCV activities, including excellent activities in biochemicalassays against HCV proteases representing various HCV genotypes,superior activities in standard HCV replicon assays including activityagainst 1a-H77 and 1b-con1 HCV strains in the absence or presence of 40%human plasma, and/or excellent activities in transient replicon assaysagainst drug-resistant mutants in a number of different HCV geneticbackgrounds.

The contents of all references (including literature references, issuedpatents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated herein in their entireties by reference. Unless otherwisedefined, all technical and scientific terms used herein are accorded themeaning commonly known to one with ordinary skill in the art.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents of the specificembodiments of the invention described herein. Such equivalents areintended with be encompassed by the following claims.

What is claimed:
 1. A method of preparing a compound of formula I, or apharmaceutically acceptable salt thereof:

the method comprising deprotecting

to form

which is then reacted with H-G to form said compound, wherein PG_(N) isan amino protecting group and PG_(C) is a carboxylic acid protectinggroup; J is absent, optionally substituted alkylene, optionallysubstituted alkenylene, optionally substituted alkynylene, —C(O)—,—O—C(O)—,—N(R₃)—C(O)—, —C(S)—, —C(═NR₄)—, —S(O)—, —S(O₂)—, or —N(R₃)—; Ais optionally substituted alkyl, optionally substituted alkenyl, oroptionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl,optionally substituted arylalkyl, optionally substituted alkoxy,optionally substituted heteroaryl, optionally substituted heterocyclic,or optionally substituted carbocyclic; Each R₁ is independently selectedfrom (i) halogen, hydroxy, amino, —CN, —CF₃, —N₃, —NO₂, —OR₄, —SR₄,—SOR₄, —SO₂R₄, —N(R₃)S(O)₂—R₄, —N(R₃) S(O₂)NR₃R₄, —NR₃R₄, —C(O)OR₄,—C(O)R₄, —C(O)NR₃R₄, or —N(R₃)C(O)R₄; (ii) optionally substituted aryl;(iii) optionally substituted heteroaryl; (iv) optionally substitutedheterocyclic; (v) optionally substituted carbocyclic; or (vi) optionallysubstituted alkyl, optionally substituted alkenyl, or optionallysubstituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selectedfrom O, S, or N; G is -E-R₅; wherein E is absent; optionally substitutedalkylene, optionally substituted alkenylene, optionally substitutedalkynylene, each containing 0, 1, 2, or 3 heteroatoms selected from O,S, or N; or —O—, —S—, —N(R₃)—, —N(R₃)S(O_(p))—, —N(R₃)C(O)—, —N(R₃)C(O)S(O_(p))—, —OS(O_(p))—, —C(O)S(O_(p))—, or —C(O)N(R₃)S(O_(p))—; p is0, 1, or 2; R₅ is H; optionally substituted alkyl, optionallysubstituted alkenyl, or optionally substituted alkynyl, each containing0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionallysubstituted carbocyclic, optionally substituted heterocyclic, optionallysubstituted aryl, or optionally substituted heteroaryl; R₃ and R₄ areeach independently selected at each occurrence from the following:optionally substituted alkyl, optionally substituted alkenyl oroptionally substituted alkynyl, each containing 0, 1, 2, or 3heteroatoms selected from O, S, or N; optionally substituted aryl;optionally substituted heteroaryl; optionally substituted heterocyclic;optionally substituted carbocyclic; or hydrogen; L is absent or isselected from optionally substituted alkylene, optionally substitutedalkenylene or optionally substituted alkynylene, each containing 0, 1,2, or 3 heteroatoms selected from O, S, or N; Y is N or —C(R″)—; whereinA, R₁, R′ and/or R″ can be taken together form a ring; j=0, 1, 2, 3, or4; k=0, 1, 2, or 3; m=0, 1, or 2; n is 0, 1, 2, 3, or 4;

denotes a carbon-carbon single or double bond, wherein if Y is N, thenR′ is optionally substituted heterocyclic or optionally substitutedcarbocyclic, and comprises two or more fused rings, and wherein R′ isnot

wherein if Y is —C(R″)—, then R′ and R″ taken together with the carbonatoms to which they are attached form an aryl or heteroaryl ring, eachsaid ring is optionally substituted; provided that said compound is nottert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate.2. The method of claim 1, wherein R′ is H, Y is N, and wherein k=3, j=1,and L is absent.
 3. The method of claim 2, wherein R₁ is hydrogen orhalogen, E is —NHS(O)— or —NHS(O₂)—, and R₅ is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, pyridinyl, pyrimidinyl, furanyl,thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, morpholinyl, piperidinyl,piperazinyl, or imidazolyl, each of which is optionally substituted. 4.The method of claim 2, wherein J is —C(O)— and A is optionallysubstituted —C₁-C₈ alkyl, containing 0, 1, 2, or 3 heteroatoms selectedfrom O, S, or N; optionally substituted aryl, optionally substituted—C₁-C₈ alkoxy, optionally substituted heteroaryl, optionally substituted—C₃-C₁₂ cycloalkyl, or optionally substituted —C₃-C₁₂ heterocycloalkyl.5. The method of claim 1, wherein Y is —C(R″)—, and R′ and R″ takentogether with the carbon atoms to which they are attached form an arylor heteroaryl ring, each said ring is optionally substituted, andwherein k=3, j=1 and L is absent.
 6. The method of claim 5, wherein R₁is hydrogen or halogen; E is —NHS(O)— or —NHS(O₂)—, and R₅ iscyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,pyridinyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl,pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, or imidazolyl, eachof which is optionally substituted.
 7. The method of claim 5, wherein Jis —C(O)— and A is optionally substituted —C₁-C₈ alkyl, containing 0, 1,2, or 3 heteroatoms selected from O, S, or N; optionally substitutedaryl, optionally substituted —C₁-C₈ alkoxy, optionally substitutedheteroaryl, optionally substituted —C₃-C₁₂ cycloalkyl, or optionallysubstituted —C₃-C₁₂ heterocycloalkyl.
 8. The method of claim 5, whereinR′ and R″ together form an optionally substituted aryl.
 9. The method ofclaim 5, wherein R′ and R″, and the atoms to which each is attached,form an aryl which is substituted by (R₂)_(x), wherein each R₂ isindependently selected from (i) halogen, hydroxy, amino, —CN, —CF₃, —N₃,—NO₂, —OR₄, —SR₄, —SOR₄, —SO₂R₄, —NHS(O₂)—R₄, —NHS(O₂)NR₃R₄, —NR₃R₄,—C(O)OR₄, —C(O)R₄, —C(O)NR₃R₄, or —N(R₃)C(O)R4; (ii) optionallysubstituted aryl; (iii) optionally substituted heteroaryl; (iv)optionally substituted heterocyclic; (v) optionally substitutedcarbocyclic; or (iv) optionally substituted alkyl, optionallysubstituted alkenyl, or optionally substituted alkynyl, each containing0, 1, 2, or 3 heteroatoms selected from O, S, or N; and x is 0, 1, 2, 3,or
 4. 10. The method of claim 1, wherein the compound of formula I isselected from the following: (2)(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(isonicotinamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(3)(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(2-fluorobenzamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(4)N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide;(5)(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(6)N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)isoxazole-5-carboxamide;(7)N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)thiazole-4-carboxamide;(8)(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(9)(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(10)(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1,3-dimethyl-1H-pyrazole-4-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(11)(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(3-fluorobenzamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(12) tert-butyl(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;(13)N-((2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide;(14)(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(15)(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(16)(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-6-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;and (17)(2R,6S,13aS,14aR,16aS,Z)-2-(3-(benzofuran-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide.11. The method of claim 1, wherein the compound of formula I is selectedfrom the following: (24) tert-butyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;(25)(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-6-(pyrazine-2-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(26) Cyclopentyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;(27)(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(5-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(28)N-((2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide;(29)(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(30)N-((2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)thiazole-5-carboxamide;(31)(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(2-fluorobenzamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(32)(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-6-(pyridazine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(33)(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)-6-(pyrimidine-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(34)(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(1-methyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(35)(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(2-hydroxy-2-methylpropanamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(36)(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(1,5-dimethyl-1H-pyrazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;(37) Cyclopentyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(2-fluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;(38) tert-Butyl(2R,6S,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(2,9-difluorophenanthridin-6-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;(39) tert-butyl(2R,6S,13aR,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;(40) Cyclopentyl(2R,6S,13aR,14aR,16aS)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate;and (41) tert-Butyl(2R,6S,13aR,14aR,16aS)-5,16-dioxo-2-(phenanthridin-6-yloxy)-14a-(thiophen-2-ylsulfonylcarbamoyl)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate.12. The method of claim 1, wherein E is —N(R₃)S(O_(p))—, R₃ is H, p is2, and R₅ is optionally substituted carbocyclic.
 13. The method of claim12, wherein R₅ is optionally substituted cyclopropyl.
 14. The method ofclaim 1, wherein E is —N(R₃)S(O_(p))—, R₃ is H, p is 2, and R₅ isoptionally substituted heteroaryl.
 15. The method of claim 1, wherein Jis —C(O)— and A is optionally substituted heteroaryl.
 16. The method ofclaim 15, wherein A is substituted heteroaryl.
 17. The method of claim15, wherein A is pyrazinyl.